Treatment of psychosis using 1-cycloalkylpiperidines

ABSTRACT

There are provided cycloalkyl piperidine compounds which are useful in the treatment of physiological or drug-induced psychosis or dyskinesia in a mammal. These novel compounds are selective sigma receptor antagonists and have a low potential for movement disorder side effects associated with typical antipsychotic agents.

RELATED APPLICATION

This is a division of application Ser. No. 07/570,199, filed Aug. 20,1990, now U.S. Pat. No. 5,109,002, which is a continuation-in-part ofapplication Ser. No. 07/404,813, filed Sep. 8, 1989 now abandoned.

FIELD OF THE INVENTION

This invention relates to novel cycloalkylpiperidine compounds,pharmaceutical compositions containing them and methods of using thesecompounds to treat physiological or drug induced psychosis and asantidyskinetic agents.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,225,608 (Uhl et al.) discloses phenoxyalkylamines of theformula:

    AR--O--R

wherein:

Ar is phenyl optionally substituted with 1 or 2 substituents selectedfrom the group:

F, Cl, Br, alkyl or alkoxy each of 1 to 4 carbon atoms, cycloalkoxy of 3to 6 carbon atoms, CF₃, CN, alkylthio of 1 to 4 carbon atoms, SCF₃, OHor alkanoyloxy of 1 to 10 carbon atoms;

R is (1-R¹ -2-pyrrolidyl)--CH₂ --CHR² --, (1-R¹ -2-piperidyl)-CH₂ --CHR²-- or 1-R¹ -3-Z-4-hexahydroazepinyl;

R¹ is H, alkyl or alkenyl each of up to 4 carbon atoms,cyclopropylmethyl or benzyl;

R² is H, alkyl of 1 to 4 carbon atoms or phenyl; and

Z is alkyl of 1 to 4 carbon atoms with the proviso that Ar isp-fluorophenyl only if R is not 2-(1-methyl-2-piperidyl)-ethyl. Thephenoxyalkylamine compounds have antidepressant activity.

Japanese patent 48-40779 (Dainippon) describes the process for preparingcompounds of the formula: ##STR1## wherein: R¹ is H, halogen, alkyl,alkoxy or trihalomethyl; and

R² is alkyl, alkenyl, hydroxyalkyl, cycloalkylalkyl, dimethylaminoalkyl,aralkyl, arylalkenyl, arylalkoxy, aryloxyalkyl,2-halophenothiazinyl(10)-propyl, 10, 11-dihydro-5H-dibenzo(b,f)azepin-5-yl-propyl or 3-halo-10,11-dihydro-5H-dibenzo (b,f)azepinylpropyl.

These compounds are described as being useful as pharmaceuticals sincethey exhibit psychotropic effects, however, no utility is actuallydocumented.

Nagai et al. (Dainippon) describe psychotropic compounds of the formula:##STR2## wherein: R¹ is H, Cl or F; and

R² is alkyl, alkenyl, benzyl, phenethyl, hydroxyethyl, cyclopropylmethylor substituted phenylalkyl.

See: Chemical Pharmaceutical Bulletin 25(8) 1911-1922 (1979).

The 3-isomers described in Japanese Patent 48-40779 and in the ChemicalPharmaceutical Bulletin, cited above, do not show the sigma receptorselectivity demonstrated by the compounds of the present invention. Itis this sigma receptor selectivity of the compounds of the presentinvention which makes them so advantageous over the compounds in theprior art. Traditionally, antipsychotic agents have been potent dopaminereceptor antagonists. For example, phenothiazines such as chlorpromazineand most butyrophenones such as haloperidol are potent dopamine receptorantagonists. These dopamine receptor antagonists are associated with ahigh incidence of side effects, particularly Parkinson-like motoreffects or extra-pyramidal side-effects (EPS), and dyskinesias includingtardive dyskinesias at high doses. Many of these side effects are notreversible even after the dopamine receptor antagonist agent isdiscontinued.

The present invention is related to antipsychotic agents which areselective sigma receptor antagonists rather than the traditionaldopamine receptor blockers known in the art, and therefore the compoundsof the present invention have low potential for the typical movementdisorder side-effects associated with the dopamine antagonistantipsychotic agents while they maintain the ability to antagonizeaggressive behavior and antagonize hallucinogenic-induced behavior.

SUMMARY OF THE INVENTION

The antipsychotic compounds of the the present invention arecycloalkylpiperidines of the formula: ##STR3## or a pharmaceuticallyacceptable salt thereof, wherein: m is 0 to 3;

n is 0 to 3;

provided that m and n are not both O;

p is 0 to 3;

X is O, S, SO, SO₂, NR⁶, CR⁷ R⁸, ##STR4## or CHOH; R¹, R³ and R⁷independently are H, alkyl of 1 to 5 carbon atoms, halogen, NR¹⁰ R¹¹,OH, CO₂ H, carboalkoxy of 2 to 6 carbon atoms, CN, Ar¹, alkoxy of 1 to 5carbon atoms or alkylthio of 1 to 5 carbon atoms;

R², R⁴ and R⁸ independently are H, alkyl of 1 to 5 carbon atoms,carboalkoxy of 2 to 6 carbon atoms, CN, alkoxy of 1 to 5 carbon atoms orAr¹ ;

provided that R¹, R², R³ and R⁴ are not alkoxy of 1 to 5 carbon atoms,alkylthio of 1 to 5 carbon atoms, NR¹ OR¹¹ or OH when X is O, S, SO, SO₂or NR⁶ ;

R⁵ is H, alkyl, halogen, OH or alkenyl;

R⁶ is H, alkyl of 1 to 5 carbon atoms or Ar¹ ;

Ar and Ar¹ independently are naphthyl, pyridyl, pyrimidyl, indolyl,quinolinyl, isoquinolinyl, or phenyl optionally substituted with alkylof 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, haloalkyl of 1 to3 carbon atoms and 1 to 7 halogen atoms, SH, S(O)_(t) alkyl of 1 to 3carbon atoms, where t is 1, 2 or 3, dialkylamino of 2 to 6 carbon atoms,halogen, OH, alkylamino of 1 to 3 carbon atoms, NH₂, CN, NO₂, SO₃ H,tetrazole, CO₂ H, carboalkoxy of 2 to 6 carbon atoms, CONH₂, SO₂ NH₂,COR⁹, CONR¹² R¹³, SO₂ NR¹² R¹³, Ar², OAr² or SAr² ;

Ar² is naphthyl or phenyl optionally substituted with alkyl of 1 to 3carbon atoms, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms,alkoxy of 1 to 3 carbon atoms, halogen or alkylthio of 1 to 3 carbonatoms;

R⁹, R¹⁰, R¹¹, R¹² and R¹³ independently are H, alkyl of 1 to 5 carbonatoms or phenyl or R¹⁰ and R¹¹ taken together are an alkylene chain of 3to 6 carbon atoms or R¹² and R¹³ taken together are an alkylene chain of3 to 6 carbon atoms; and

a or b is a double bond or a single bond, provided that both are notdouble bonds.

Preferred compounds in the present invention are those compounds ofFormula (I) wherein:

X is ##STR5## CHOH or O; and/or m is 0; and/or

n and p are 1; and/or

R³ -R⁵ are H; and/or

Ar is phenyl optionally substituted with halogen,

OCH₃, NH₂, NO₂ or another phenyl group.

Specifically preferred compounds of the present invention are:

a) 1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine

b) 1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine, hydrobromide salt

c) 1-(cyclopropylmethyl)-4-(2'-(4"-chlorophenyl)-2'-oxoethyl) piperidine

d) 1-(cyclopropylmethyl)-4-(2'-(4"-chlorophenyl)-2'-oxoethyl)piperidine, hydrobromide salt

e) 1-(cyclopropylmethyl)-4-(4'-fluorophenoxymethyl)piperidine

f) 1-(cyclopropylmethyl)-4-(4'-fluorophenoxymethyl)piperidine,hydrochloride salt

g) 1-(cyclopropylmethyl)-4-(4'-chlorophenoxymethyl)piperidine

h) 1-(cyclopropylmethyl)-4-(4'-chlorophenoxymethyl)piperidine,hydrochloride salt

i) 1-(cyclopropylmethyl)-4-(4'-nitrophenoxymethyl)piperidine

j) 1-(cyclopropylmethyl)-4-(2'-(4"-biphenyl)-2'-oxoethyl)piperidine

k) 1-(cyclopropylmethyl)-4-(2'-(4"-biphenyl)-2'-oxoethyl)piperidine,hydrobromide salt.

Also provided in the present invention are pharmaceutical compositionscomprising an effective amount of a compound of Formula (I) and apharmaceutically acceptable carrier.

Further provided are methods of using the compounds of Formula (I) forthe treatment of physiological or drug-induced psychosis in a mammal aswell as for the treatment of dyskinesias in a mammal.

Furthermore, there are provided, processes for the preparation ofcompounds of Formula (I).

In addition, there are provided novel intermediate compounds and methodsof preparing them, useful for the preparation of some of the activecompounds of this invention; said intermediate compounds having theformula: ##STR6## wherein: m is 0 to 3;

n is 0 to 3;

provided that m and n are not both O;

p is 1 to 3;

X is O, S, NR⁶ ;

Ar and Ar¹ independently are naphthyl pyridyl, pyrimidyl, quinolinyl,isoquinolinyl or phenyl optionally substituted with

alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, haloalkylof 1 to 3 carbon atoms and 1 to 7 halogen atoms, S(O)_(t) alkyl of 1 to3 carbon atoms, where t is 1, 2 or 3, dialkylamino of 2 to 6 carbonatoms, halogen, alkylamino of 1 to 3 carbon atoms, CN, NO₂, carboalkoxyof 2 to 6 carbon atoms, COR⁹, CONR¹² R¹³, SO₂ NR¹² R₁₃, Ar², OAr² orSAr² ;

Ar² is naphthyl or phenyl optionally substituted with alkyl of 1 to 3carbon atoms, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms,alkoxy of 1 to 3 carbon atoms, halogen or alkylthio of 1 to 3 carbonatoms;

R¹ -R⁴ and R⁶ independently are H, alkyl of 1 to 5 carbon atoms or Ar¹ ;

R⁵ is H, alkyl, halogen, OH or alkenyl; and

R⁹, R¹² and R¹³ independently are H, alkyl of 1 to 5 carbon atoms orphenyl, or R¹² and R¹³ taken together are an alkylene chain of 3 to 6carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of Formula (I) may be prepared according to Scheme I. InScheme I, a compound of Formula (II) [where X is O, S, NR⁶ or CH₂ (whenm=1 and CR¹ R² ═CO) or a single bond (when m=1)] is treated with a basein an inert solvent then reacted with a compound of Formula (III) toafford a compound of Formula (IV). Bases which may be used for thisreaction include, but are not limited to, alkali metal hydrides,preferably sodium hydride, alkali metal carbonates, preferably potassiumcarbonate, alkali metal dialkylamides, preferably lithiumdi-isopropylamide, alkali metal bis(trialkylsilyl) amides, preferablysodium bis(trimethylsilyl)amide, alkyl alkali metal compounds (such asbutyl lithium), alkali metal alkoxides (such as sodium ethoxide), alkylalkaline earth metal halides (such as methyl magnesium bromide),trialkylamines (such as triethylamine or di-isopropylethylamine),polycyclic di-amines (such as 1,4 diazabicyclo [2.2.2]octane or1,8-diazabicyclo-[5.4.0)undecene) or quaternary ammonium salts (such asTriton B). The choice of inert solvent must be compatible with thechoice of base (see J. March, Advanced Organic Chemistry (New York:J.Wiley and Sons, 1985) pp. 255-446; H. O. House, Modern SyntheticReactions (New York:W. A. Benjamin Inc., 1972, pp. 546-553)). Solventsinclude lower alkyl alcohols of 1 to 6 carbons, dialkyl ethers of 4 to10 carbons, cyclic ethers of 4 to 10 carbons, preferably tetrahydrofuranor dioxane, dialkylformamides, preferably N,N-dimethylformamide,dialkylacetamides, preferably N,N-dimethylacetamide, cyclic amides,preferably N-methylpyrrolidinone, hydrocarbons of 5 to 10 carbons oraromatic hydrocarbons to 6 to 10 carbons. The leaving group Y in Formula(III) may be halide, arylsulfonyloxy, preferably p-toluenesulfonyloxy,alkylsulfonyloxy (such as methanesulfonyloxy), haloalkylsulfonyloxy,preferably trifluoromethylsulfonyloxy or acyloxy, preferably acetoxy.Reaction temperatures range from about -78° to 200° C., preferably about50°-100° C. Compounds of Formula (IV) may be treated with reducingagents in inert solvents to afford compounds of Formula (I). Suchreducing agents include but are not limited to, alkali metal aluminumhydrides, preferably lithium aluminum hydride, alkali metalborohydrides, preferably lithium borohydride, alkali metaltrialkoxyaluminum hydrides (such as lithium tri-t-butoxyaluminumhydride), dialkylaluminum hydrides (such as di-isobutylaluminumhydride), borane, dialkylboranes (such as di-isoamyl borane), alkalimetal trialkylboron hydrides (such as lithium triethylboron hydride).Inert solvents include lower alkyl alcohols of 1 to 6 carbons, etherealsolvents (such as diethyl ether or tetrahydrofuran), aromatic ornon-aromatic hydrocarbons of 6 to 10 carbons. Reaction temperatures forthe reduction range from about -78° to 200° C., preferably about 50° to120° C. The choice of reducing agent and solvent is known to thoseskilled in the art as taught in the above cited March reference (pp.1093-1110). ##STR7##

In Scheme II, a compound of Formula (II) (X=O, S, NR⁶) is reacted with acompound of Formula (V) in the presence of a triarylphosphine, (Ar"3P),preferably triphenylphosphine and an azodicarboxylate diester (RO₂CN═NCO₂ R) wherein R is lower alkyl, and preferably diethylazodicarboxylate in an inert solvent, preferably tetrahydrofuran orbenzene. Reaction temperatures range from about 50° to 80° C. Thechoices of triaryl phosphine, solvent or azodicarboxylate ester areknown to those skilled in the art as described by O. Mitsunobu(Synthesis, 1 [1981]). ##STR8##

In Scheme III a pyridine derivative of Formula (VII) is converted to itsmetallo derivative (VII*) by treatment with a metallating agent. For thecase where n=1 or Y=H, such metallating agents are bases, which includebut are not limited to, alkali metal dialkylamides, preferably lithiumdi-isopropylamide, alkali metal bis(trialkylsilyl)amides, preferablylithium or sodium bis(trimethylsilyl)amides, alkali metal alkoxides,alkali metal hydrides, alkyl alkaline earth metal halides (such asmethyl magnesium bromide). For the cases where n is not equal to 1 or Yis halogen, preferably Cl or Br, metallating agents include alkalimetals, such as lithium, alkaline earth metals, such as magnesium, oralkyl lithiums, such as n-butyl lithium. Metallating agents includecombinations of one of the above reagents and an inorganic salt such asalkaline earth metal halides or transition metal halides, preferablyCuBr, ZnCl₂ or CeCl₃. The metallo derivative of (VII), i.e. (VII*) maybe formed in an inert solvent such as lower alkyl alcohols of 1 to 6carbons, ethereal solvents, such as tetrahydrofuran or1,2-dimethoxyethane, or aromatic or non-aromatic hydrocarbons of 6 to 10carbon atoms. Temperatures for the metallation range from about -80° C.to 200° C., preferably about -78° to 70° C. once the metallo derivativeof (VII), i.e. (VII*) is formed, it is reacted in the same solvent witha compound of Formula (VI) (where R is alkoxyl of 1 to 6 carbons orhalogen) to afford a compound of Formula (VIII). Reaction temperaturesrange from about -78° to 70° C., preferably about 0° to 70° C. Acompound of Formula (VIII) is then converted to a compound of Formula(X) upon treatment with an alkylating agent of Formula (IX) (Z=halogen,alkylsulfonyloxy, or haloalkylsulfonyloxy). Such alkylation can beconducted with or without an inert solvent. When an inert solvent isused, such solvent may be a lower alkyl alcohol of 1 to 6 carbons, analkanenitrile, preferably acetonitrile, a halocarbon of 1 to 6 carbons,a dialkylformamide of 2 to 6 carbons, a dialkylacetamide of 3 to 7carbons or an aromatic or non-aromatic hydrocarbon of 6 to 10 carbons.The intermediate (X) may be isolated upon removal of volatiles,chromatography or crystallization or (X) may be carried on to the nextstep in Scheme III if it is hygroscopic. Treatment of a compound ofFormula (X) with a reducing agent yields a compound of Formula (I)(where X=CHOH or C=O [depending on the reducing agent]). Reducing agentsinclude molecular hydrogen and a noble metal catalyst, preferablypalladium on carbon or platinum IV oxide, alkali metal aluminumhydrides, preferably lithium aluminum hydride, alkali metaltrialkoxyaluminum hydrides, dialkylaluminum hydrides, alkali metalborohydrides, preferably sodium borohydride, dialkylboron hydrides,di-imide and its precursors, alkali metal cyanoborohydrides, preferablysodium cyanoborohydride, zinc amalgam or zinc metal. It will be apparentto those skilled in the art that some of the above reagents bythemselves will only partially reduce the pyridine ring to givetetrahydropyridines among other products (See generally: the above citedMarch reference, pp. 1093-1110), for example structure (X'): ##STR9## Inthese cases, combinations of the above reagents either in tandem orsequentially must be used. Inert solvents include, but are not limitedto, lower alkyl alcohols, ethereal solvent such as diethyl ether ortetrahydrofuran, aromatic or non-aromatic hydrocarbons of 6 to 10carbons. ##STR10##

According to Scheme IV, an ester of Formula (XI) (R is alkyl of 1 to 6carbons or aralkyl of 7 to 10 carbons) is treated with an alkylatingagent of Formula (IX) in the presence of a base and an inert solvent.The bases and inert solvents that may be used are the same as thosedefined for the first reaction step of Scheme I. The resulting ester ofFormula (XII) is then converted to an aldehyde of Formula (XIII) eitherdirectly using a reducing agent or indirectly using a reducing agentthen an oxidizing agent in sequence. In the latter course, theintermediate alcohol (XIV) may or may not be isolated depending on itsstability using standard techniques known to those skilled in the art.Reducing agents and the inert solvents for the reduction include thosedefined in Schemes I and III. Oxidizing agents for converting an alcoholof Formula (XIV) to an aldehyde of Formula (XIII) include transitionmetal oxides, such as CrO₃ or MnO₂, pyridine-chromium complexes, such asCrO₃.C₅ H₅ N, pyridinium dichromate or pyridinium chlorochromate, anoxalylchloride-dimethylsulfoxide-triethylamine reagent system, commonlycalled the Swern oxidation system (D. Swern et al., J. Organic. Chem.,43, 2480-2482 (1978)) or a dimethyl sulfoxide-dicyclohexylcarbodiimidesystem (See: H. O. House, Modern Synthetic Reactions (New York:W. A.Benjamin Inc., 1972) pp. 416-421). Such oxidations, when necessary,employ an inert solvent such as those employed for the reduction orhalocarbons of 1 to 6 carbons, preferably dichloromethane or1,2-dichloroethane. A compound of Formula (XIII) is then converted to acompound of Formula (XVI) [Formula (I) where X=CHOH] by reaction with ametallo derivative of a compound of Formula (XV). Such a metalloderivative is prepared by treatment with a base (X=H) or othermetallating agents (X=halogen). Metallating agents, and the inertsolvents for such metallations, include those defined for the first stepof Scheme III. A compound of Formula (XVI) [Formula (I) where X=CHOH] isoxidized to a compound of Formula (XVII) (Formula (I) where X=CO] usingan oxidizing agent and inert solvent, both of which are defined the sameas for the second step of Scheme IV. ##STR11##

Alternatively, some of the compounds of this invention may be preparedusing the procedures shown in Scheme V. A compound of Formula (XVIII) isconverted to its metallo derivative with either a base (if Y=H, halogen)or other metallating agents (if Y=halogen) in an inert solvent. Thechoices of metallating agent and inert solvent are defined as for thefirst step of Scheme III. Such a metallo derivative is reacted with analdehyde of Formula (XIX) in the same inert solvent to afford a compoundof Formula (XVI) [Formula (I) where X=CHOH]. Reaction temperatures rangefrom about -100° to 200° C. preferably about -78° to 80° C. ##STR12##

Some of the compounds of this invention may be prepared according toScheme VI. A compound of Formula (XVII) [Formula (I) where X=CO] isreacted with an amine of Formula HNR¹⁰ R¹¹ in the presence of a reducingagent in an inert solvent to give a compound of Formula (XX) [Formula(I) where X=CHNR¹⁰ R¹¹ ]. The choices of reducing agent and inertsolvent are defined the same as for these in the last step of SchemeIII. R¹⁰ and R¹¹ independently may be H or alkyl of 1 to 6 carbons ortaken together are an alkylene chain of 2 to 6 carbons. When R¹⁰ and R¹¹are both H, an ammonium salt is used (preferably ammonium acetate)according to the prior art (see pp. 45-100 of House, Modern SyntheticReaction, cited supra). ##STR13##

According to Scheme VII, a compound of Formula (XVI) [Formula I whereX=CHOH] is treated with a sulfonylating agent, preferablymethanesulfonyl chloride, p-toluenesulfonyl chloride ortrifluoromethanesulfonic anhydride, in the presence of a base, such as atrialkylamine, preferably triethylamine, an alkali metal hydride,preferably sodium hydride, an aromatic amine, preferably pyridine, or analkali metal carbonate or alkoxide. Such a sulfonylation is performed inan inert solvent such as a halocarbon of 1 to 6 carbons, preferablydichloromethane, ethereal solvents, such as diethylether ortetrahydrofuran, aromatic or non-aromatic hydrocarbons of 6 to 10carbons, or alkanenitriles, preferably acetonitrile. A compound ofFormula (XXI) [preferably where X is O₂ SCH₃, O₂ SC₆ H₄ -CH₃ -p or O₂SCF₃ ] is formed from such a sulfonylation and then is reacted with anucleophilic reagent in an inert solvent to afford a compound of Formula(XXII) [Formula (I) where X is CHR⁷ ]. Such nucleophilic reagentsinclude alkali metal alkoxides, alkali metal aluminum hydrides, dialkylaluminum hydrides, dialkylboranes, alkyl alkaline earth halides,preferably alkyl magnesium halides, dialkyl lithium cuprates, amines ofthe formula HNR¹⁰ R¹¹, wherein R¹⁰ and R¹¹ are as defined above, alkalimetal cyanides or alkali metal alkylsulfides. Inert solvents includelower alkyl alcohols, alkanenitrile, preferably acetonitrile, etherealsolvents, such as diethyl ether and tetrahydrofuran, aromatic ornon-aromatic hydrocarbons of 6 to 10 carbon atoms.

According to Scheme VIII, a compound of Formula (XVII) [Formula (I)where X=CO] is reacted with a nucleophilic reagent in an inert solventto give a compound of Formula (XXIII) [Formula (I) where X=CR⁶ R⁷ whereR⁶ and R⁷ are as defined in Formula (I)]. The choice of solvent isdefined the same as for those in Scheme VII. The nucleophilic reagentsinclude alkali metal hydrides, dialkyl aluminum hydrides, trialkylaluminum compounds, aryl or alkyl alkaline earth halides (preferablyaryl or alkyl magnesium halides), aryl or alkyl lithiums ordialkyllithium cuprates. ##STR14##

According to Scheme IX an acid derivative of Formula (XXIV) [R ishalogen, OH or lower alkoxy and Ar and R³ and R⁴ are as defined inFormula (i)] is reacted with an aromatic compound in the presence of aLewis acid in an inert solvent to afford a compound of Formula (XXV).Lewis acids include aluminum halides, alkylsulfonic acids, preferablymethanesulfonic acid, polyphosphoric acid, or acetic acid. Inertsolvents include carbon disulfide or aromatic hydrocarbons of 6 to 10carbons bearing electron-withdrawing substituents, such as nitrobenzene.Compounds of Formula (XXV) are then converted to pyridinium salts (XXVI)with alkylating agents (IX). These compounds of Formula (XXVI) are thentreated with reducing agents in an inert solvent to afford compounds ofFormula (XXVII) [Formula (I), wherein m is O and X is CO]. The choicesof alkylating agent (IX), reducing agent, inert solvents and reactiontemperatures are the same as those defined in Scheme III. ##STR15##

Alternatively, according to Scheme X, a compound of Formula (XXVIII) isreacted with an aromatic compound in the presence of a Lewis acid and aninert solvent to provide a compound of Formula (XXIX). The choices ofLewis acid and inert solvents are defined the same as those in SchemeIX. Reaction temperatures range from about 0° to 150° C. Compounds ofFormula (XXIX) may be treated with reducing agents in inert solvents togive compounds of Formula (XXX) [Formula (I) wherein m is O and X isCHOH]. The choices of reducing agent, solvent and reaction temperatureare defined the same as those for the second step of Scheme I. Compoundsof Formula (XXX) may be oxidized to compounds of Formula (XXXI) [Formula(I) wherein m is O and X=CO]. The choices of oxidizing agents, solventsand reaction temperatures are defined the same as those for theoxidation of compounds of Formula (XIV) to compounds of Formula (XIII)in Scheme (IV). ##STR16##

Compounds of Formula (I) may also be made according to Scheme XI. Acompound of formula ArZ is reacted with a compound of Formula (XXXII) (Xis O, S or NR⁶) in the presence of a base and an inert solvent to yielda compound of Formula (XXXIII) [Formula (I) wherein m is O]. Ar ispreferably a phenyl ring substituted with an electron withdrawing groupor a heteroaryl ring. Z is halogen, preferably fluorine or chlorine. Thechoices for base and solvent are as defined in the first step of SchemeI. ##STR17##

Compounds of Formula (I) may also be prepared according to Scheme XII. Acompound of Formula (XXXIV) [wherein Z is halogen, preferably fluorine]is reacted with a compound MY [M is an alkali metal or an alkaline earthmetal and Y is a nucleophile selected from the group: azide, alkoxide of1 to 6 carbon atoms, alkylthioxide of 1 to 6 carbon atoms, cyanide,halide, NH₂, alkylamide of 1 to 6 carbon atoms or dialkylamide of 2 to 6carbon atoms] in an inert solvent at a reaction temperature of about25°-200° C. and preferably 100°-150° C., to yield a compound of FormulaXXXV [Formula I, wherein m is 0 and X is C=O]. The inert solvent may bethe same as those defined in the first step of Scheme I. Compounds offormula MY may be generated in situ from a compound of formula HY andabase chosen from the bases defined for the first step of Scheme I.##STR18##

EXPERIMENTAL SECTION

Analytical data were recorded for the compounds described below usingthe following general procedures. Infrared spectra were recorded on aPerkin-Elmer Model 1600 FT-IR spectrometer; absorbances are recorded incm⁻¹ and intensities are denoted s (strong), m (moderate) and w (weak).Proton NMR spectra were recorded on a IBM-Bruker FT-NMR spectrometer(200 MH_(z) or 300 MHz); chemical shifts were recorded in ppm (δ) froman internal tetramethylsilane standard in deuterochloroform ordeuterodimethylsulfoxide and coupling constants (i) are reported in Hz.Mass spectra (MS) or high resolution mass spectra (HRMS) were recordedon Finnegan MAT 8230 spectrometer or Hewlett Packard 5988A modelspectrometer. Melting points were recorded on a Buchi Model 510 meltingpoint apparatus and are uncorrected. Boiling points are uncorrected.

Reagents were purchased from commercial sources and, where necessary,purified prior to use according to the general procedures outlined by D.D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals,3rd ed., (New York:Pergamon Press, 1988). Chromatography was performedon silica gel using the solvent systems indicated below. For mixedsolvent systems, the volume ratios are given. Parts and percentages areby weight unless otherwise specified.

Intermediate compounds of Formula (IV) (where X=O) are exemplified inthe following Tables 1-5, these intermediate compounds are then furtherreduced by various processes to yield some of the active antipsychoticcompounds of Formula (I) (Tables 6-10). Compounds of Formula (I) arefurther exemplified in Tables 11-17.

EXAMPLE 1 Synthesis of1-(Cyclopropylmethyl)-4-(4-fluorophenoxymethyl)piperidine A.1-(Cyclopropylcarbonyl)-4-hydroxymethylpiperidine

A solution of 1-(cyclopropylcarbonyl)-4-carboethoxy piperidine (35 g,156 mmol) in anhydrous tetrahydrofuran (350 mi) was stirred at ambienttemperature under a nitrogen atmosphere. A solution of lithiumborohydride in tetrahydrofuran (2 M, 78 ML, 156 mmol) was addeddropwise. Trimethyl borate (1.77 mL, 15.7 mmol) was added, then thereduction mixture was stirred for about 48 hours. Water was addeddropwise with vigorous stirring until the vigorous gas evolution ceased.The mixture was diluted twofold with water and extracted three timeswith ethyl acetate. The combined organic layers were dried overmagnesium sulfate, filtered and concentrated in vacuo. Vacuumdistillation (bp 165° C., 0.5 mm Hg) gave a clear, colorless liquid(18.2 g):IR (neat): 3410 (br s), 3094 (w), 3008 (s), 2918 (s), 2858 (s),1738 (m), 1613 (s), 1448 (s), 1375 (s), 1316 (s); ¹ H-NMR: 4.7-4.5 (m,1H), 4.4-4.1 (m, 1H), 3.6-3.4 (m, 2H), 3.2-2.5 (m, 3H), 2.0-1.7 (m, 4H),1.4-1.1 (m, 1H), 1.0-0.8 (m, 2H), 0.8-0.65 (m, 2H); HRMS:Calcd for C₁₀H₁₇ NO₂ :183.1259; Found: 183.1250; Anal.:Calcd for C₁₀ H₁₇ NO₂ : C,65.54, H, 9.35, N, 7.64; Found: C, 65.83, H, 9.43, N, 7.50.

B. 1-(Cyclopropylcarbonyl)-4-(methanesulfonyloxy)piperidine

A solution of 1-(cyclopropylcarbonyl)-4-hydroxymethyl-piperidine fromStep A (6.0 g, 33 mmol) and triethylamine (11.9 g, 16.4 mL, 118 mmol) indichloromethane (150 mi) was stirred at about 0° C. under a nitrogenatmosphere. A solution of methanesulfonyl chloride (4.5 g, 3.0 mL, 39mmol) in dichloromethane (20 mL) was added dropwise. The reactionmixture was then stirred at about 0°-5° C. for 35 minutes. The paleyellow turbid mixture was poured into a separatory funnel, washed oncewith a 1N hydrochloric acid solution (ice-cold, 100 mL), twice with asaturated sodium bicarbonate solution (100 mL) and once with brine (100mL). The organic solution was dried over magnesium sulfate, filtered andconcentrated in vacuo to give a pale yellow oil (8.5 g): ¹ H-NMR:4.8-4.5 (m, 1H), 4.4-4.2 (m, 1H), 4.2-3.95 (m, 2H), 3.2-2.8 (m, 4H),2.7-2.5 (m, 1H), 2.2-1.6 (m, 4H), 1.5-1.1 (m, 2H), 1.05-0.9 (m, 2H),0.85-0.7 (m, 2H) ; MS:261.

C. 1-(Cyclopropylcarbonyl)-4-(4'-fluorophenoxymethyl)piperidine

Sodium hydride (50% in oil, 1.0 g, 20 mmol) was washed with hexanestwice, then suspended in anhydrous tetrahydrofuran (20 mL) with stirringunder a nitrogen atmosphere. A solution of 4-fluorophenol (2.13 g, 19mmol) in tetrahydrofuran (10 mL) was added dropwise with vigorous gasevolution. The reaction mixture was stirred at room temperature for 15minutes, then a solution of1-cyclopropylcarbonyl-4-methanesulfonyloxypiperidine (983 mg, 3.77 mmol)from Step B, in tetrahydrofuran (10 mL) was added dropwise. The reactionmixture was then stirred at reflux temperature for about 22 hours,cooled to ambient temperature, poured onto a 2N sodium hydroxidesolution and mixed. The aqueous mixture was extracted three times withether; the combined organic layers were washed with a 2N sodiumhydroxide solution, dried over magnesium sulfate and filtered. Solventwas removed in vacuo to give a yellow liquid.

Column chromatography (ethyl acetate) gave, after removal of solvent invacuo, the product, a clear, colorless liquid (617 mg): ¹ H-NMR:7.05-6.75 (m, 4H), 4.8-4.55 (br m, 1H), 4.45-4.2 (m, 1H), 3.9-3.6 (br s,2H), 3.25-3.0 (br t, 1H, J=6), 2.8-2.5 (br t, 1H, J=6), 2.2-1.7 (m, 4H),1.5-1.2 (m, 2H), 1.05-0.9 (m, 2H), 0.8-0.7 (m, 2H); HRMS:Calcd for C₁₆H₂₀ FNO₂ :277.1478; Found: 277.1466; Anal.:Calcd for C₁₆ H₂₀ FNO₂:C,69.29, H, 7.27, N, 5.05, F, 6.85; Found: C, 69.14, H, 7.41, N, 5.04,F, 7.04.

D. 1-(Cyclopropylmethyl)-4-(4¹ -fluorophenoxymethyl)-piperidine

A solution of 1-(cyclopropylcarbonyl)-4-(4¹-fluorophenoxymethyl)piperidine (316 mg, 1.14 mmol) in anhydroustetrahydrofuran (5 mL) was stirred at ambient temperature under anitrogen atmosphere. A solution of lithium aluminum hydride intetrahydrofuran (1 M, 10 mL, 10 mmol) was added dropwise via syringe.The reaction mixture was then stirred at reflux temperature for 24hours, then it was cooled to room temperature. Ethyl acetate (10 mL) wasadded dropwise, then water (0.5 mL), a 2N sodium hydroxide solution (0.5mL), water (1.5 mL) were added sequentially. The resulting suspensionwas filtered through Celite® the inorganic salts were washed withcopious amounts of ethyl acetate. The filtrate was dried over magnesiumsulfate and filtered. Solvent was removed in to give the product, a paleyellow white solid (266 mg, 89% yield): ¹ H-NMR:7.0-76.7 (m, 4H), 3.7(d, 3H, J=7), 3.05 (br d, 2H, J=10), 2.2 (d, 2H, J=7), 2.0-1.6 (m, 4H),1.5-1.25 (m, 2H), 0.95-0.75 (m, 1H), 0.65-0.5 (m, 2H), 0.1-0.0 (m, 2H);MS:263; Anal.: Calcd. for C₁₆ H₂₂ FNO 0.5H₂ O: C, 70.50, H, 8.23, N,5.52; Found: C, 70.49, H, 8.44, N, 5.14.

The compounds of Table 1 may be prepared by the method described inExample 1C using the appropriate hydroxy aromatic compound and theappropriate polar solvent.

                  TABLE 1                                                         ______________________________________                                         ##STR19##                    (II)                                            Ex.       R                mp (°C.)                                    ______________________________________                                         1C       4-F              (a)                                                 2        4-Cl              82-83 (b)                                          3        4-CH.sub.3 O      54-56 (c)                                          4        H                                                                    5        4-Br                                                                 6        4-I                                                                  7        4-NO.sub.2                                                           8        4-(CH.sub.3).sub.2 N                                                 9        4-NHCOCH.sub.3                                                       10       4-CH.sub.3                                                           11       4-t-C.sub.4 H.sub.9                                                                            105-109 (d)                                         12       4-C.sub.2 H.sub.5 O                                                  13       4-NHCHO                                                              14       4-CO.sub.2 CH.sub.3                                                                            111-112 (e)                                         15       4-COCH.sub.3      98-101 (f)                                         16       4-SCH.sub.3      107-109 (g)                                         17       4-SO.sub.2 N(CH.sub.3).sub.2                                         18       4-CF.sub.3                                                           19       4-CCl.sub.3                                                          20       4-CH.sub.2 CF.sub.3                                                  21       4-COCF.sub.3                                                         22       4-CH.sub.2 CH.sub.2 F                                                23       4-SCOCH.sub.3                                                        24       4-CN                                                                 25       4-CON(CH.sub.3).sub.2                                                26       4-N.sub.3                                                            27       4-CHCH.sub.2                                                         28       4-C.sub.6 H.sub. 5                                                                             (h)                                                 29       3-Cl                                                                 30       3-Br                                                                 31       3-I                                                                  32       3-F                                                                  33       3-CH.sub.3 O                                                         34       3-C.sub.2 H.sub.5 O                                                  35       3-CH.sub.3                                                           36       3-C.sub.2 H.sub.5                                                    37       3-CO.sub.2 CH.sub.3                                                  38       3-COCH.sub.3                                                         39       3-CF.sub.3                                                           40       3-CCl.sub.3                                                          41       3-CH.sub.2 CF.sub.3                                                  42       3-COCF.sub.3                                                         43       3-CH.sub.2 CH.sub.2 F                                                44       3-CN                                                                 45       3-CON(CH.sub.3).sub.2                                                46       3-CHO                                                                47       3-N.sub.3                                                            48       3-NHCHO                                                              49       3-NHCOCH.sub.3                                                       50       3-NO.sub.2                                                           51       3-(CH.sub.3).sub.2 N                                                                           (i)                                                 52       3-SCH.sub.3                                                          53       3-SO.sub.2 N(CH.sub.3).sub.2                                         54       3-SCOCH.sub.3                                                        55       2-F                                                                  56       2-Br                                                                 57       2-Cl                                                                 58       2-I                                                                  59       2-CH.sub.3 O                                                         60       2-CH.sub.3                                                           61       2-CO.sub.2 CH.sub.3                                                  62       2-COCH.sub.3                                                         63       2-CF.sub.3                                                           64       2-CCl.sub.3                                                          65       2-CH.sub.2 CF.sub.3                                                  66       2-COCF.sub.3                                                         67       2-CH.sub.2 CH.sub.2 F                                                68       2-CN                                                                 69       2-CON(CH.sub.3).sub.2                                                70       2-CHO                                                                71       2-N.sub.3                                                            72       2-NHCHO                                                              73       2-NHCOCH.sub. 3                                                      74       2-NO.sub.2                                                           75       2-SCH.sub.3                                                          76       3,4-F.sub.2      (j)                                                 77       3,4-Cl.sub.2     (k)                                                 78       3,4-(CH.sub.3 O).sub.2                                               79       2,6-Br.sub.2 -4-CH.sub.3                                             80       2,6-Br.sub.2 -4-NO.sub.2                                             81       2,4-Cl.sub.2 -6-NO.sub.2                                             82       2,4-Cl.sub.2                                                         83       3,5-Cl.sub.2                                                         84       3-(C.sub.2 H.sub.5).sub.2 N                                          85       2,4-F.sub.2                                                          86       2,3-F.sub.3                                                          87       2,3-(CH.sub.3 O).sub.2                                               88       3,4-(CH.sub.3).sub.2                                                 89       2,4-(CH.sub.3).sub.2                                                 90       2,4-(NO.sub.2).sub.2                                                 91       3-(OC.sub.2 H.sub.5)4-OCH.sub.3                                      92       4-(OCH.sub.3)-3(OC.sub.2 H.sub.5)                                    93       5-F-2-NO.sub.2                                                       94       2-(CH.sub.3 O)-4-(NO.sub.2)                                          95       3-(CH.sub.3 O)-4-(NO.sub.2)                                          96       3,4-OCH.sub.2 O                                                      97       3-CH.sub.3 -4-NO.sub.2                                               98       4-CH.sub.3 -3-NO.sub.2                                               99       2-CH.sub.3 -3-NO.sub.2                                              100       2-NO.sub.2 -3-CH.sub.3                                              101       F.sub.5          (l)                                                102       Br.sub.5                                                            103       Cl.sub.5                                                            104       2,3,5,6-F.sub.4                                                     105       2,3,5,6-Cl.sub.4                                                    106       2,3,5,6-Br.sub.4                                                    107       2,4,5-F.sub.3                                                       108       2,4,5-Cl.sub.3                                                      109       2,4,5-Br.sub.3                                                      110       3,4,5-(CH.sub.3 O).sub.3                                                                       108-110 (m)                                        111       4-C.sub.6 H.sub.5 O                                                                            109-110 (n)                                        112       4-F-C.sub.6 H.sub.4                                                                            133-135 (o)                                        113       4-CH.sub.3 OC.sub.6 H.sub.4                                                                    143-145 (p)                                        ______________________________________                                         Footnotes for Table 1                                                         (a) Anal.: Calcd for C.sub.16 H.sub.20 FNO.sub.2 : C, 69.29, H, 7.27, N,      5.05, F, 6.85; Found: C, 69.14, H, 7.41, N, 5.04, F, 7.04.                    (b) Anal.: Calcd for C.sub.16 H.sub.20 ClNO.sub.2 : C, 65.41, H, 6.86, N,     4.77, Cl, 12.07; Found: C, 65.18, H, 6.77, N, 4.67, Cl, 12.14.                (c) Anal.: Calcd for C.sub.17 H.sub.23 NO.sub.3 : C, 70.56, H, 8.01, N,       4.84; Found: C, 70.59, H, 8.02, N, 4.94.                                      (d) .sup.1 HNMR(CDCl.sub.3): 7.4-7.2(m, 2H), 6.9-6.7(m, 2H), 4.8-4.6(m,       1H), 3.9-3.7(m, 2H), 3.2-3.0(m, 1H), 2.7-2.5(m, 1H), 2.1-1.7(m, 3H),          1.5-1.3(m, 7H), 1.3(s, 9H); MS: 315.                                          (e) Anal.: Calcd for C.sub.18 H.sub.23 NO.sub.4 : C, 68.12, H, 7.30, N,       4.41; Found: C, 68.20, H, 7.48, N, 4.63.                                      (f) .sup.1 HNMR(CDCl.sub.3): 8.0(d, 2H, J=8), 6.9(d, 2H, J=8), 4.7(m, 1H)     4.4(m, 1H), 3.9(m, 2H), 3.2(m, 1H), 2.7(m, 1H), 2.6(s, 3H), 2.2-1.7(m,        4H), 1.4(m, 2H); MS: 301.                                                     (g) Anal.: Calcd for C.sub.17 H.sub.23 NO.sub.2 S: C, 66.85, H, 7.59, N,      4.58, S, 10.67; Found: C, 66.92, H, 7.74, N, 4.46, S, 10.23                   (h) .sup.1 HNMR(CDCl.sub.3): 7.6-7.2(m, 7H), 7.0(d, 2H, J=7), 4.8-4.6(m,      1H), 4.4-4.2(m, 1H), 3.9(br s, 2H), 3.3-3.1(m, 2H), 2.8-2.6(m, 2H),           2.2-1.7(m, 3H), 1.4-1.2(m, 1H), 1.1-0.9(m, 2H), 0.9-0.7(m, 2H).               (i) .sup.1 HNMR(CDCl.sub.3): 7.15(t, 1H, J=8), 6.15(d, 1H, J=9),              6.1-6.0(m, 2H), 4.7-4.55(m, 1H), 4.35-4.2(m, 1H), 3.9-3.7(m, 2H),             3.2-3.0(m, 1H), 2.9(s, 6H), 2.8-2.5(m, 1H), 2.2-1.7(m, 4H), 1.5-1.2(m,        2H), 1.05-0.9(m, 2H), 0.8-0.65(m, 2H); HRMS: Calcd for C.sub.18 H.sub.26      N.sub.2 O.sub.2 : 302.1994; Found: 302.1994.                                  (j) .sup.1 HNMR(CDCl.sub.3, 300MHz): 7.05(q, 1H, J=8), 6.75-6.65(m, 1H),      6.65-6.5(m, 1H), 4.75-4.6(m, 1H), 4.4-4.2(m, 1H), 3.85-3.7(m, 2H), 3.15(b     t, 1H, J=7), 2.65(br t, 1H, J=7), 2.15-1.7(m, 4H), 1.5-1.2(m, 2H),            1.1-0.9(m, 2H), 0.9-0.75(m, 2H); HRMS: Calcd for C.sub.16 H.sub.19 F.sub.     NO.sub.2 : 295.1384; Found: 295.1385                                          (k) .sup.1 HNMR(CDCl.sub.3): 7.4-7.2(m, 1H), 7.05-6.95(m, 1H), 6.8-6.65(m     1H), 4.8-4.55(m, 1H), 4.4-4.2(m, 1H), 3.9-3.7(m, 2H), 3.3-3.0(m, 1H),         2.8-2.5(m, 1H), 2.2-1.7(m, 4H), 1.5-1.2(m, 2H), 1.06-0.9(m, 2H),              0.85-0.7(m, 2H); HRMS: Calcd for C.sub.16 H.sub.19 Cl.sub.2 NO.sub.2 :        327.0793; Found: 327.0788.                                                    (l) .sup.1 HNMR(CDCl.sub.3): 4.75-4.55(m, 1H), 4.4-4.2(m, 1H), 4.1-3.9(m,     2H), 3.25-3.05(m, 1H), 2.75-2.5(m, 1H), 2.2-1.7(m, 3H), 1.5-1.2(m, 2H),       1.05-0.9(m, 2H), 0.85-0.6(m, 2H); Calcd for C.sub.16 H.sub.16 F.sub.5         NO.sub.2 : 329.1101; Found: 349.1100.                                         (m) Anal.: Calcd for C.sub.19 H.sub.27 NO.sub.5 : C, 65.31, H, 7.79, N,       4.01; Found: C, 65.41, H, 7.76, N, 4.26.                                      (n) Anal.: Calcd for C.sub.22 H.sub.25 NO.sub.2 : C, 75.19, H, 7.17, N,       3.99; Found: C, 75.15, H, 7.12, N, 3.91.                                      (o) .sup.1 HNMR(DMSO, 300MHz): 7.65(dd, 2H, J=8, 6), 7.55(d, 2H, J=8),        7.3(t, 2H, J=8), 7.05(d, 2H, J=8), 4.5-4.3(m, 2H), 3.9(d, 2H, J=7),           3.2-3.0(m, 1H), 2.7-2.55(m, 1H), 2.1-1.7(m, 4H), 1.4-1.05(m, 2H),             0.85-0.6(m, 4H); MS: 354.                                                     (p) .sup.1 HNMR(DMSO, 300MHz): 7.55(2 x d, 4H, J=8), 7.0(d, 4H, J=8),         4.5-4.3(m, 2H), 3.9(d, 2H, J=7), 3.8(s, 3H), 3.2-3.1(m, 1H), 2.7-2.6(m,       1H), 2.1-1.75(m, 4H), 1.35-1.1(m, 2H), 0.8-0.6(m, 4H); HRMS: Calcd for        C.sub.23 H.sub.27 NO.sub.3 : 365.1991; Found: 365.2001.                  

The compounds of Table 2 may be prepared by the method described inExample 1C using the appropriate hydroxy aromatic compound and theappropriate polar solvent.

                  TABLE 2                                                         ______________________________________                                         ##STR20##                    (II)                                            Ex.        Ar                mp (°C.)                                  ______________________________________                                        114        2-naphthyl        150-152 (a)                                      115        1-naphthyl                                                         116        2,4-dichloro-1-naphthyl                                            117        4-indolyl                                                          118        5-indolyl                                                          119        5-isoquinolinyl                                                    120        4-pyridyl         (b)                                              121        3-pyridyl                                                          122        2-methyl-4-quinolinyl                                              123        3-nitro-2-pyridyl                                                  124        4-quinolinyl      (c)                                              125        5-quinolinyl                                                       126        5-pyrimidyl                                                        ______________________________________                                         Footnotes for Table 2                                                         (a) Anal.: Calcd for C.sub.20 H.sub.23 NO.sub.2.0.2H.sub.2 O: C, 76.75, H     7.53, N, 4.47; Found: C, 76.91, 76.89, H, 7.60, 7.53, N, 4.56, 4.32.          (b) .sup.1 HNMR(CDCl.sub.3): 8.45(d, 2H, J=6), 6.8(d, 2H, J=6), 4.7(br d,     1H, J=10), 4.3(br d, 1H, J=10), 3.95-3.8(m, 2H), 3.15(br t, 1H, J=10),        2.65(br t, 1H, J=10), 2.2-1.75(m, 4H), 1.5-1.25(m, 2H), 1.05-0.95(m, 2H),     0.8-0.65(m, 2H); HRMS: Calcd for C.sub.15 H.sub.20 N.sub.2 O.sub.2 :          260.1525; Found: 260.1537.                                                    (c) .sup.1 HNMR(CDCl.sub.3): 8.7(d, 1H, J=6), 8.2(d, 1H, J=8), 8.05(d, 1H     J=8), 7.7(td, 1H, J=6, 1), 7.5(t, 1H, J= 6), 6.7(d, 1H, J=6), 4.75(br d,      1H, J=10), 4.35(br d, 1H, J=10), 4.15-4.0(m, 2H), 3.2(br t, 1H, J=10,         2.7(br t, 1H, J=10); HRMS: Calcd for C.sub.19 H.sub.22 N.sub.2 O.sub.2 :      310.1681; Found: 310.1690.                                               

The compounds of Table 3 may be prepared according to the proceduredescribed for Example 1C using the appropriate hydroxymethyl aromaticcompound and polar solvent.

                  TABLE 3                                                         ______________________________________                                         ##STR21##                    (II)                                            Ex.          R              mp (°C.)                                   ______________________________________                                        127          4-F                                                              128          4-Cl                                                             129          4-Br                                                             130          4-I                                                              131          H                                                                132          4-CH.sub.3 O                                                     133          4-C.sub.2 H.sub.5 O                                              134          4-TBDMSO       (a)                                               135          4-NO.sub.2                                                       136          4-(CH.sub.3).sub.2 N                                             137          4-NHCOCH.sub.3                                                   138          4-N.sub.3                                                        139          4-CH.sub.3                                                       140          4-C.sub.2 H.sub.5                                                141          4-CO.sub.2 CH.sub.3                                              142          4-COCH.sub.3                                                     143          4-CF.sub.3                                                       144          4-CHO                                                            145          4-CN                                                             146          4-CON(CH.sub.3).sub.2                                            147          4-SCH.sub.3                                                      148          3-F                                                              149          3-Cl                                                             150          3-Br                                                             151          3-I                                                              152          3-CH.sub.3 O                                                     153          3-C.sub.2 H.sub.5 O                                              154          3-CH.sub.3                                                       155          3-C.sub.2 H.sub.5                                                156          3-CO.sub.2 CH.sub.3                                              157          3-COCH.sub.3                                                     158          3-CF.sub.3                                                       159          3-CN                                                             160          3-CON(CH.sub.3).sub.2                                            161          3-CHO                                                            162          3-N.sub.3                                                        163          3-NO.sub.2                                                       164          3-NHCOCH.sub.3                                                   165          3-NHCHO                                                          166          3-(CH.sub.3).sub.2 N                                             167          3-SCH.sub.3                                                      168          3-SO.sub.2 N(CH.sub.3).sub.2                                     169          2-F                                                              170          2-Cl                                                             171          2-Br                                                             172          2-I                                                              173          2-CH.sub.3 O                                                     174          2-CH.sub.3                                                       175          2-CO.sub.2 CH.sub.3                                              176          2-COCH.sub.3                                                     177          2-CF.sub.3                                                       178          2-CN                                                             179          2-N.sub.3                                                        180          2-NHCHO                                                          181          2-NHCOCH.sub.3                                                   182          2-NO.sub.2                                                       183          2-SCH.sub.3                                                      184          3,4-F.sub.2                                                      185          3,4-Cl.sub.2                                                     186          3,4-(CH.sub.3 O).sub.2                                           187          2,4-Cl.sub.2                                                     188          2,4-F.sub.2                                                      189          2,4-(CH.sub.3 O).sub.2                                           190          3,4-F.sub.2                                                      191          3,5-Cl.sub.2                                                     192          3,4-(CH.sub.3).sub.2                                             193          2,4-(NO.sub.2).sub.2                                             194          3,4-(NO.sub.2).sub.2                                             195          3-CH.sub.3 O-4-NO.sub.2                                          196          4-CH.sub.3 O-3-NO.sub.2                                          197          3,4-OCH.sub.2 O                                                  198          F.sub.5                                                          199          Cl.sub.5                                                         200          3,4,5-(CH.sub.3 O).sub.3                                         ______________________________________                                         Footnote for Table 3                                                          (a) TBDMS = tbutyldimethylsilyl.                                         

The compounds of Table 4 may be prepared according to the methoddescribed in Example 1C using the appropriate hydroxy aromatic compoundand the appropriate polar solvent.

                  TABLE 4                                                         ______________________________________                                         ##STR22##                    (II)                                            Ex.           Ar            mp (°C.)                                   ______________________________________                                        201           2-naphthyl                                                      202           1-naphthyl                                                      203           2-quinolinyl                                                    204           4-quinolinyl                                                    205           2-pyridyl                                                       206           3-pyridyl                                                       207           4-pyridyl                                                       208           2-pyrimidyl                                                     209           2-furyl                                                         210           2-thienyl                                                       ______________________________________                                    

The compounds of Table 5 may be prepared according to the method ofExample 1C using the appropriate 4-methanesulfonyloxypiperidinederivative.

                  TABLE 5                                                         ______________________________________                                         ##STR23##                    (II)                                            Ex.       TR                   Notes                                          ______________________________________                                        211       1-CH.sub.3                                                          212       2-CH.sub.3           (a)                                            213       2,2-Cl.sub.2 -1-CH.sub.3                                                                           (b)                                            214       2,2-(CH.sub.3).sub.2 -3-(CHC(CH.sub.3).sub.2)                       215       2,2(CH.sub.3).sub.2 -3-(CHCCl.sub.2)                                216       2,2-Cl.sub.2                                                        217       2-F                                                                 218       2-Cl                                                                219       1-OH                                                                220       2,2,3,3-(CH.sub.3).sub.4                                            ______________________________________                                         Footnotes for Table 5                                                         (a) .sup.1 HNMR(CDCl.sub.3, 300MHz): 6.95(t, 2H, J=7), 6.8(dd, 2H, J=7,       6), 4.65(br d, 1H, J=8), 4.25(br d, 1H, J=8), 3.9-3.7(m, 2H), 3.15(br t,      1H, J=8), 2.65(br t, 1H, J=8), 2.15-1.8(m, 3H), 1.5-1.1(m, 5H), 1.15(d,       3H, J=7), 0.65-0.45(m, 1H); HRMS: Calcd for C.sub.17 H.sub.22 FNO.sub.2 :     291.1634; Found: 291.1636.                                                    (b) .sup.1 HNMR(CDCl.sub.3, 300MHz): 7.05-6.9(m, 2H), 6.9-6.8(m, 2H),         4.65(br t, 1H, J=10), 3.95(br t, 1H, J=10), 3.9-3.75(m, 2H), 3.35-3.2(m,      1H), 2.8-2.65(m, 1H), 2.2-2.0(m, 2H), 2.0-1.9(m, 1H), 1.7-1.2(m, 4H),         1.55(d, 3H, J=7); HRMS: Calcd for C.sub.17 H.sub.20 Cl.sub.2 FNO.sub.2 :      359.0855; Found: 359.0860.                                               

Compounds of Formula (I) are exemplified in the following Tables 6-17.

The compounds of Tables 6, 7, 8, 9 and 10 may be prepared employing theprocedure described for Example 1D with the appropriate1-(cyclopropylcarbonyl)piperidine derivative (Examples 2-220) and theappropriate reducing agent.

                  TABLE 6                                                         ______________________________________                                         ##STR24##                                                                    Ex.       R                 mp (°C.)                                   ______________________________________                                        1D        4-F               (a)                                               221       4-Cl              (b)                                               222       4-CH.sub.3 O       37-39 (c)                                        223       H                  54-56 (d)                                        224       4-Br                                                                225       4-I                                                                 226       4-NH.sub.2                                                          227       4-(CH.sub.3).sub.2 N                                                228       4-NHC.sub.2 H.sub.5                                                 229       4-CH.sub.3                                                          230       4-C.sub.6 H.sub.5  81-83 (e)                                        231       4-C.sub.2 H.sub.5 O                                                 232       4-NHCH.sub.3                                                        233       4-CH.sub.2 OH     120-121 (f)                                       234       4-t-C.sub.4 H.sub.9                                                                              84-86 (g)                                        235       4-SCH.sub.3       (h)                                               236       4-SO.sub.2 N(CH.sub.3).sub.2                                        237       4-CF.sub.3                                                          238       4-CCl.sub.3                                                         239       4-CH.sub.2 CF.sub.3                                                 240       4-CH(OH)CH.sub.3  125-127 (i)                                       241       4-CH.sub.2 CH.sub.3 F                                               242       4-SH                                                                243       4-CH.sub.2 NH.sub.2                                                                             (j)                                               244       4-CH.sub.2 N(CH.sub.3).sub.2                                        245       4-CHCH.sub.2                                                        246       3-Cl                                                                247       3-Br                                                                248       3-I                                                                 249       3-F                                                                 250       3-CH.sub.3 O                                                        251       3-C.sub.2 H.sub.5 O                                                 252       3-CH.sub.3                                                          253       3-C.sub.2 H.sub.5                                                   254       3-CH.sub.2 OH                                                       255       3-CH(OH)CH.sub.3                                                    256       3-CF.sub.3                                                          257       3-CH.sub.2 CF.sub.3                                                 258       3-CH(OH)CF.sub.3                                                    259       3-CH.sub.2 CH.sub.2 F                                               260       3-CH.sub.2 NH.sub.2                                                 261       3-CH.sub.2 N(CH.sub.3).sub.2                                        262       3-NHCH.sub.3                                                        263       3-NHC.sub.2 H.sub.5                                                 264       3-NH.sub.2                                                          265       3-N(CH.sub.3).sub.2                                                 266       3-SCH.sub.3                                                         267       2-F                                                                 268       2-Br                                                                269       2-Cl                                                                270       2-I                                                                 271       2-CH.sub.3 O                                                        272       2-CH.sub.3                                                          273       2-CH.sub.2 OH                                                       274       2-CH(OH)CH.sub.3                                                    275       2-CF.sub.3                                                          276       2-CH.sub.2 CF.sub.3                                                 277       2-CH.sub.2 NH.sub.2                                                 278       2-CH.sub.2 N(CH.sub.3).sub.2                                        279       2-NHCH.sub.3                                                        280       2-NHC.sub.2 H.sub.5                                                 281       2-NH.sub.2                                                          282       2-SCH.sub.3                                                         283       3,4-F.sub.2       (k)                                               284       3,4-Cl.sub.2                                                        285       3,4-(CH.sub.3 O).sub.2                                              286       2,6-Br.sub.2 -4-CH.sub.3                                            287       2,6-Br.sub.2 -4-NH.sub.2                                            288       2,4-Cl.sub.2 -6-NH.sub.2                                            289       2,4-Cl.sub.2                                                        290       3,5-Cl.sub.2                                                        291       3-(C.sub.2 H.sub.5).sub.2 N                                         292       2,4-F.sub.2                                                         293       2,3-F.sub.2                                                         294       2,3-(CH.sub.3 O).sub.2                                              295       3,4-(CH.sub.3).sub.2                                                296       2,4-(CH.sub.3).sub.2                                                297       2,4-(NH.sub.2).sub.2                                                298       3-(OC.sub.2 H.sub.5)-4-(OCH.sub.3)                                  299       4-(OCH.sub.3)-3-(OC.sub.2 H.sub.5)                                  300       5-F-2-NH.sub.2                                                      301       2-CH.sub.3 O-4-NH.sub.2                                             302       3-CH.sub.3 O-4-NH.sub.2                                             303       3-4-OCH.sub.2 O                                                     304       3-CH.sub.3 -4-NH.sub.2                                              305       4-CH.sub.3 -3-NH.sub.2                                              306       2-CH.sub.3 -3-NH.sub.2                                              307       2-NH.sub.2 -3-CH.sub.3                                              308       F.sub.5           (l)                                               309       Br.sub.5                                                            310       Cl.sub.5                                                            311       2,3,5,6-F.sub.4                                                     312       2,3,5,6-Cl.sub.4                                                    313       2,4,5-F.sub.3                                                       314       2,3,5-Cl.sub.3                                                      315       2,4,5-Br.sub.3                                                      316       3,4,5-(CH.sub.3 O).sub.3                                                                        (m)                                               ______________________________________                                         Footnotes for Table 6                                                         (a) .sup.1 HNMR: 7.0-7.0-6.7(m, 4H), 3.7(d, 3H, J=7), 3.05(br d, 2H,          J=10), 2.2(d, 2H, J=7), 2.0-1.6(m, 6H), 1.5-1.25(m, 2H), 0.95-0.75(m, 1H)     0.65-0.5(m, 2H), 0.1-0.0(m, 2H), MS: 263.                                     (b) .sup.1 HNMR(200MHz, CDCl.sub.3 -DMSO): 7.7(d, 2H, J=8), 7.35(d, 2H,       J=8), 4.3-4.2(m, 2H), 3.6-3.4(m, 2H), 2.65(d, 2H, J=6), 2.5-2.1(m, 4H),       1.96-1.7(m, 2H), 1.4-1.2(m, 1H), 1.0-0.85(m, 2H), 0.6-0.5(m, 2H); HRMS:       Calcd for C.sub.16 H.sub.21 ClNO: 279.1390; Found 279.1376.                   (c) .sup.1 HNMR(200MHz, CDCl.sub.3 -DMSO): 7.15(s, 4H), 4.25-4.1(m, 2H),      4.2(s, 3H), 3.6-3.4(m, 2H), 2.65(d, 2H, J=7), 2.55-2.1(m, 5H),                1.95-1.75(m, 2H), 1.4-1.25(m, 1H), 1.0-0.85(m, 2H), 0.6-0.45(m, 2H).          (d) Anal.: Calcd for C.sub.16 H.sub.23 NO: C, 78.26, H, 9.37, N, 5.71;        Found: C, 77.94, H, 9.49, N, 5.55.                                            (e) Anal.: Calcd for C.sub.22 H.sub.27 NO.0.125 H.sub.2 O: C, 81.67, H,       8.43, N, 4.33; Found: C, 81.86, 81.85, H, 8.64, 8.71, N, 4.13, 4.05.          (f) Anal.: Calcd for C.sub.17 H.sub.25 NO.sub.2.0.3 H.sub.2 O: C, 72.72,      H, 9.19, N, 4.99; Found: C, 72.98, 73.08, H, 9.04, 9.10, N, 4.97, 4.96.       (g) Anal.: Calcd for C.sub.20 H.sub.31 NO: C, 79.73, H, 10.30, N, 4.65;       Found: C, 79.71, H, 10.18, N, 4.72.                                           (h) .sup.1 HNMR(CDCl.sub.3, 300MHz): 7:15(d, 2H, J=8), 6.75(d, 2H, J=8),      3.7(d, 2H, J=7), 3.05(br d, 2H, J=9), 2.25(s, 3H), 2.15(d, 2H, J=7),          2.0-1.6(m, 5H), 1.45-1.3(m, 2H), 0.9-0.7(m, 1H), 0.5-0.35(m, 2H),             0.1-0.0(m, 2H); HRMS: Calcd for C.sub.17 H.sub.25 NOS: 291.1657; Found:       291.1653.                                                                     (i) Anal.: Calcd for C.sub.18 H.sub.27 NO.sub.2 : C, 74.96, H, 9.09, N,       4.85; Found: C, 74.77, H, 9.38, N, 4.75.                                      (j) .sup.1 HNMR(CDCl.sub.3, 300MHz): 7.15(d, 2H, J=8), 6.8(d, 2H, J=8),       3.75(d, 2H, J=7), 2.9(br d, 2H, J=10), 2.1(d, 2H, J=7), 1.9-1.5(m, 6H),       1.3-1.1(m, 3H), 0.85-0.7(m, 1H), 0.55-0.45(m, 2H), 0.1-0.0(m, 2H).            (k) .sup.1 HNMR(CDCl.sub.3, 300MHz): 6.95(q, 1H, J=8), 6.65-6.5(m, 1H),       6.5-6.4(m, 1H), 3.65(d, 2H, J=7), 3.05(br d, 2H, J=10), 2.2(d, 2H, J=7),      2.0-1.8(m, 2H), 1.8-1.6(m, 3H), 1.5-1.3(m, 2H), 0.9-0.7(m, 1H),               0.65-0.5(m, 2H), 0.10-0.0(m, 2H); MS: 281.                                    (l) .sup.1 HNMR(CDCl.sub. 3): 6.15(s, 2H), 3.85(s, 6H), 3.8(s, 2H),           3.75(d, 3H, J=7), 3.15(br d, 2H, J=10), 2.3(d, 2H, J=7), 2.1-1.7(m, 5H),      1.65-1.4(m, 2H), 1.0-0.8(m, 1H), 0.6-0.45(m, 2H), 0.15-0.05(m, 2H), HRMS:     Calcd for C.sub.19 H.sub.29 NO.sub.4 : 335.2096; Found: 335.2105.             (m) .sup.1 HNMR(CDCl.sub.3, 200MHz): 4.0(d, 2H, J=7), 3.15(br d, 2H,          J=10), 2.3(d, 2H, J=7), 2.05(br t, 2H, J=7)1.9-1.7(m, 3H), 1.5-1.35(m,        2H), 0.95-0.85(m, 1H), 0.55-0.45(m, 2H), 0.15-0.05(m, 2H); HRMS: Calcd fo     C.sub.16 H.sub.18 F.sub.5 NO: 335.1308; Found: 335.1304.                 

                  TABLE 7                                                         ______________________________________                                         ##STR25##                     (I)                                            Ex.       Ar                 mp (°C.)                                  ______________________________________                                        317       2-naphthyl         69-71 (a)                                        318       1-naphthyl                                                          319       2-4-dichloro-1-naphthyl                                             320       4-indolyl                                                           321       5-indolyl                                                           322       5-isoquinolinyl                                                     323       4-pyridyl          53-54 (b)                                        324       3-pyridyl                                                           325       2-methyl-4-quinolinyl                                               326       4-quinolinyl       85-86 (c)                                        327       5-quinolinyl                                                        328       5-pyrimidyl                                                         ______________________________________                                         Footnotes for Table 7                                                         (a) Anal.: Calcd for C.sub.20 H.sub.25 NO.0.25H.sub.2 O: C, 80.09, H,         8.58, N, 4.67; Found: C, 80.30, 80.40, H, 8.58, 8.65, N, 4.52, 4.70.          (b) Anal.: Calcd for C.sub.15 H.sub.22 N.sub.2 O.0.25H.sub.2 O: C, 71.82,     H, 8.84, N, 11.17; Found: C, 71.84, 71.86, H, 9.07, 9.07, N, 10.98, 11.06     (c) Anal.: Calcd for C.sub.19 H.sub.24 N.sub.2 O.0.75H.sub.2 O: C, 73.63,     H, 8.29, N, 9.03; Found: C, 73.59, 73.86, H, 8.33, 8.33, N, 8.71, 8.77.  

                  TABLE 8                                                         ______________________________________                                         ##STR26##                     (I)                                            Ex.         R               mp (°C.)                                   ______________________________________                                        329         4-F             (a)                                               330         4-Cl                                                              331         4-Br                                                              332         4-I                                                               333         H                                                                 334         4-CH.sub.3 O                                                      335         4-C.sub.2 H.sub.5 O                                               336         4-TBDMSO                                                          337         4-NH.sub.2                                                        338         4-(CH.sub.3).sub.2 N                                              339         4-NHC.sub.2 H.sub.5                                               340         4-CH.sub.3                                                        341         4-C.sub.2 H.sub.5                                                 342         4-CH.sub.2 OH                                                     343         4-CH(OH)CH.sub.3                                                  344         4-CF.sub.3                                                        345         4-CH.sub.2                                                        346         4-CH.sub.2 N(CH.sub.3).sub.2                                      347         4-SCH.sub.3                                                       348         3-F                                                               349         3-Cl                                                              350         3-Br                                                              351         3-I                                                               352         3-CH.sub.3 O                                                      353         3-C.sub.2 H.sub.5 O                                               354         3-CH.sub.2 OH                                                     355         3-CH(OH)CH.sub.3                                                  356         3-CF.sub.3                                                        357         3-CH.sub.2 NH.sub.2                                               358         3-CH.sub.2 N(CH.sub.3).sub.2                                      359         3-NH.sub.2                                                        360         3-NHC.sub.2 H.sub.5                                               361         3-NHCH.sub.3                                                      362         3-(CH.sub.3).sub.2 N                                              363         3-SCH.sub.3                                                       364         2-F                                                               365         2-Cl                                                              366         2-Br                                                              367         2-I                                                               368         2-CH.sub.3 O                                                      369         2-CH.sub.3                                                        370         2-CH.sub.2 OH                                                     371         2-CF.sub.3                                                        372         2-CH.sub.2 NH.sub.2                                               373         2-NH.sub.2                                                        374         3,4-F.sub.2                                                       375         3,4-Cl.sub.2                                                      376         3,4-(CH.sub.3 O).sub.2                                            377         2,4-Cl.sub.2                                                      378         2,4-F.sub.2                                                       379         2,4-(CH.sub.3 O).sub.2                                            380         3,5-F.sub.2                                                       381         3,4-Cl.sub.2                                                      382         3,4-(CH.sub.3).sub.2                                              383         2,4-(NH.sub.2).sub.2                                              384         3,4-(NH.sub.2).sub.2                                              385         4-(CH.sub.3 O)-3-NH.sub.2                                         386         3,4-OCH.sub.2 O                                                   387         F.sub.5                                                           388         Cl.sub.5                                                          389         3,4,5-(CH.sub.3 O).sub.3                                          ______________________________________                                         Footnote for Table 8                                                          (a) bp 115-137° C.(0.3 mm Hg); .sup.1 HNMR: 7.33-7.06(m, 2H),          7.03-6.97(m, 2H), 4.45(s, 2H), 3.32(d, 2H, J=6); HRMS: Calcd for C.sub.17     H.sub.24 FNO: 277.1842; Found: 277.1829; Anal.: Calcd for C.sub.17            H.sub.24 FNO: C, 73.61, H, 8.72, N, 5.05; Found: C, 72.68, 72.51, H, 9.27     8.98, N, 4.66, 4.96.                                                     

                  TABLE 9                                                         ______________________________________                                         ##STR27##                     (I)                                            Ex.           Ar            mp (°C.)                                   ______________________________________                                        390           2-naphthyl                                                      391           1-naphthyl                                                      392           2-quinolinyl                                                    393           4-quinolinyl                                                    394           2-pyridyl                                                       395           3-pyridyl                                                       396           4-pyridyl                                                       397           2-pyrimidyl                                                     398           2-furyl                                                         399           2-thienyl                                                       ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                         ##STR28##                                                                    Ex.      R                    mp (°C.)                                 ______________________________________                                        400      1-CH.sub.3                                                           401      2-CH.sub.3           (a)                                             402      2,2-Cl.sub.2 -1-CH.sub.3                                                                           (b)                                             403      2,2-(CH.sub.3).sub.2 -3-(CHC(CH.sub.3).sub.2)                        404      2,2-(CH.sub.3).sub.2 -3(CHCCl.sub.2)                                 405      2,2-Cl.sub.2                                                         406      2-F                                                                  407      2-Cl                                                                 408      1-OH                                                                 409      2,2,3,3-(CH.sub.3).sub.4                                             ______________________________________                                         Footnotes for Table 10                                                        (a) .sup.1 HNMR(CDCl.sub.3, 300MHz): 6.95(t, 2H, J=8), 6.8(dd, 2H, J=8,       6), 3.75(d, 2H, J=7), 3.2-3.0(m, 2H), 2.45(dd, 1H, J=9, 6), 2.15(dd, 1H,      J=9, 7), 2.1-1.9(m, 2H), 1.9-1.7(m, 3H), 1.55-1.4(m, 2H), 1.05(d, 3H,         J=7), 1.65-1.45(m, 2H), 0.25(t, 2H, J=7); Calcd for C.sub.17 H.sub.24 FNO     277.1842; Found: 277.1818.                                                    (b) .sup.1 HNMR(CDCl.sub.3, 300MHz): 7.0-6.9(m, 2H), 6.9-6.8(m, 2H),          3.75(d, 2H, J=7), 3.0-2.9(m, 2H), 2.55(dd, 2H, J=12, 6), 2.1-1.95(m, 2H),     1.9-1.7(m, 4H), 1.4(s, 3H), 1.5-1.3(m, 1H), 1.25(s, 2H); HRMS: Calcd for      C.sub.17 H.sub.22 FCl.sub.2 NO: 345.1063; Found: 345.1064.               

EXAMPLE 410 1-(Cyclopropylmethyl)-4-(4'-Fluorophenoxymethyl)piperidineHydrochloride Salt

A solution of 1-(cyclopropylmethyl)-4-(4'-fluorophenoxymethyl)piperidine(250 mg, 0.95 mmol) in ether (5 mi) was stirred at room temperature. A1N hydrogen chloride-ether solution (5 mi) was added dropwise. Theprecipitate was filtered and washed with copious amounts of ether.Drying in vacuo at 60° C. afforded a white powder (200 mg): mp 162°-164°C.; ¹ H-NMR (DMSO-d₆): 10.6-10.2 (m, 1H), 7.35-6.85 (m 5H), 3.9 (d, 2H,J=7), 3.6-3.4 (m, 1H), 3.35-3.1 (m, 2H), 3.05-2.75 (m, 3H), 2.1-1.5 (m,4H), 1.2-1.0 (m, 2H), 0.7-0.55 (m, 2H), 0.25-0.1 (m, 2H); Anal.: Calcdfor C₁₆ H₂₃ FNO.HCl: C, 63.88, H, 8.04, N, 4.66, F, 6.32, Cl, 11.79;Found: C, 64.08, H, 7.84, N, 4.58, F, 6.10, Cl, 11.96.

The compounds of Table 11 can be prepared using the process described inExample 410, employing the appropriate acid.

                  TABLE 11                                                        ______________________________________                                         ##STR29##                     (I)                                            Ex.   m     R.sup.1     R.sup.2                                                                              HX      mp (°C.)                        ______________________________________                                        410   0     4-F         H      HCl     162-164                                411   0     4-Cl        H      HCl     145-146 (a)                            412   0     4-CH.sub.3 O                                                                              H      HCl     125-127 (b)                            413   0     3,4,5-(CH.sub.3 O).sub.3                                                                  H      HCl     113-114 (c)                            414   0     4-CH.sub.2 OH                                                                             H      HCl                                            415   0     H           H      HCl                                            416   1     F           H      HCl     123-125 (d)                            417   1     4-CH.sub.3 O                                                                              H      HCl                                            418   0     3-(CH.sub.3).sub.2 N                                                                      H      HCl                                            419   3     F           H      HCl                                            420   0     4-CH.sub.3 S                                                                              H      HCl     157-158 (e)                            421   0     3,4-F.sub.2 H      HCl     151-152 (f)                            422   0     4-EtNH      H      HCl     130-133 (g)                            423   0     F.sub.5     H      HCl     173-174 (h)                            424   0     4-F         2,2-Cl.sub.2 -                                                                       maleate 156-157 (i)                                                    1-CH.sub.3                                            425   0     4-F         2-CH.sub.3                                                                           fumarate                                                                              115-117 (j)                            ______________________________________                                         Footnotes for Table 11                                                        (a) Anal.: Calcd for C.sub.16 H.sub.21 ClNO.HCl: C, 60.96, H, 7.03, N,        4.44, Cl, 22.49; Found: C, 60.85, H, 7.30, N, 4.43, Cl, 22.53.                (b) Anal.: Calcd for C.sub.17 H.sub.25 NO.sub.2.HCl.0.25H2O: C, 64.54, H,     8.44, N, 4.43, Cl, 11.20; Found: C, 64.53, 64.54, H, 8.43, 8.50, N, 4.32,     4.44, Cl, 11.58, 11.58.                                                       (c) .sup.1 HNMR(DMSO-d.sub.6): 10.9-10.6(m, 1H), 6.25(s, 2H), 5.5-5.1(m,      2H), 3.9-3.5(m, 5H), 2.75(s, 6H), 3.55(s, 3H), 3.1-2.8(m, 4H), 2.1-1.6(m,     4H), 1.2-1.0(m, 1H), 0.7-0.55(m, 2H), 0.45-0.3(m, 2H); Anal. Calcd for        C.sub.19 H.sub.29 NO.sub.4.1.3 HCl: C, 59.61, H, 7.97, N, 3.66, Cl, 12.04     Found: C, 59.31, 59.18, H, 8.10, 8.07, N, 3.50, 3.53, Cl, 11.67, 11.64.       (d) Anal.: Calcd for C.sub.17 H.sub.24 FNO.HCl: C, 65.06, H, 8.03, N,         4.46; Found: C, 65.16, 64.98, H, 8.18, 8.29, N, 4.29, 4.12.                   (e) Anal.: Calcd for C.sub.17 H.sub.25 NOS.HCl: C, 62.27, H, 7.68, N,         4.27, S, 9.78, Cl, 10.81; Found: C, 62.30, H, 7.91, N, 4.17, S, 9.59, Cl,     10.83.                                                                        (f) Anal.: Calcd for C.sub.16 H.sub.21 F.sub.2 NO.HCl: C, 60.47, H, 6.66,     N. 4.41, F, 11.96, Cl, 11.16; Found: C, 60.43, H, 6.78, N, 4.25, F, 11.98     C, 10.91.                                                                     (g) Anal.: Calcd for C.sub.18 H.sub.28 N.sub.2 O.2HCl.0.5H.sub.2 O: C,        58.37, H, 8.44, N, 7.56; Found: C, 58.24, 58.50, H, 9.07, 8.74, N, 7.07,      6.96.                                                                         (h) Anal.: Calcd for C.sub.16 H.sub.18 F.sub.5 NO.HCl: C, 51.69, H, 5.15,     N, 3.76, F, 25.55, Cl, 9.54; Found: C, 51.60, H, 5.07, N, 3.97, F, 25.54,     Cl, 9.39.                                                                     (i) Anal.: Calcd for C.sub.17 H.sub.22 FCl.sub.2 NO.C.sub.4 H.sub.4           O.sub.4 : C, 54.56, H, 5.66, N, 3.03, Cl, 15.34, F, 4.11; Found C, 54.47,     H, 5.67, N, 3.02, Cl, 15.00, F, 4.10.                                         (j) Anal.: Calcd for C.sub.17 H.sub.24 FNO.C.sub.4 H.sub.4 O.sub.4 : C.       61.75, H, 6.91, N, 3.43, F, 4.65; Found: C, 62.28, 62.15, H, 7.03, 7.04,      N, 3.40, 3.38, F, 4.24, 4.09.                                            

The compounds of Table 12 can be prepared using the process described inExample 410, employing the appropriate acid.

                  TABLE 12                                                        ______________________________________                                         ##STR30##                     (I)                                            Ex.      m       Ar         HX     mp (°C.)                            ______________________________________                                        426      0       2-naphthyl HCl    206-208 (a)                                427      0       4-pyridyl  HCl                                               428      0       4-quinolinyl                                                                             HCl                                               ______________________________________                                         Footnote for Table 12                                                         (a) Anal.: Calcd for C.sub.20 H.sub.25 NO.HCl: C, 72.38, H, 7.90, N, 4.22     Cl, 10.68; Found: C, 72.27, H, 8.09, N, 4.14.                            

Example 429 describes an alternate procedure to prepare the product ofExample 1.

EXAMPLE 429

Synthesis of 1-(cyclopropylmethyl)-4-(4'-Fluorophenoxymethyl)piperidine

A. Ethyl 1-(Cyclopropylcarbonyl)piperidine-4-carboxylate

(1) A solution of ethyl isonipecotate (65 g, 413 mmol) and pyridine(65.3 g, 66.8 mL, 826 mmol) in ether (500 mL) was stirred at about 0° C.under a nitrogen atmosphere. A solution of cyclopropyl-carboxylic acidchloride (43.2 g, 37.5 mL, 413 mmol) in ether (500 mL) was addeddropwise over 30 minutes. The reaction mixture was stirred while warminggradually to room temperature over 21 hours, then it was poured ontowater (1 L) and mixed. The layers were separated; the organic layer waswashed once with a 1N hydrochloric acid solution (1 L), then twice witha saturated sodium bicarbonate solution (1 L). The organic solution wasdried over magnesium sulfate and filtered. Solvent was removed in vacuoto give a clear pale yellow liquid. Vacuum distillation (bp 140°-145°C., 0.4 mm Hg) afforded a clear colorless liquid (45 g, 48% yield): ¹H-NMR: 4.5-4.25 (m, 1H), 4.15 (q, 2H, J=7), 3.35-3.05 (m, 1H), 2.96-2.7(m, 1H), 2.65-2.45 (m, 1H), 2.0-1.85 (m, 2H), 1.75-1.5 (m, 3H), 1.25 (t,3H, J=7), 1.0-0.9 (m, 2H), 0.75-0.6 (m, 2H); HRMS: Calcd for C₁₂ H₁₉ NO₃:225.1365; Found: 225.1365.

(2) Alternatively, this compound can be made as follows: Ethylisonipecotate (48 mL, 0.31 mole), (bromomethyl)cyclopropane (85%, 50 g,0.31 mole), and potassium carbonate (48 g, 0.35 mole) were stirred atroom temperature in dry ethyl alcohol (500 mL) for 23 hours. The mixturewas filtered through Celite®, rinsed with ethyl acetate and concentratedin vacuo. The resulting mixture was diluted with ethyl acetate (1 L),extracted with H₂ O (2×250 mL), dried (MgSO₄) and concentrated in vacuo.The crude product was distilled, bp 90°-115° C. at 0.8 mm Hg, to yieldthe product (33.8 g, 52%) as a colorless oil, which gave ¹ H-NMR and MSdata as listed above in Example 420 A (1).

B. 1-(Cyclopropylmethyl)-4-hydroxymethyl piperidine

(1) A solution of lithium aluminum hydride in tetrahydrofuran (1 M, 54.6mL, 54.6 mmol) was added to tetrahydrofuran (100 mL) via syringe withstirring under a nitrogen atmosphere. This solution was cooled to 0° to5° C. A solution of ethyl 1-(cyclopropyl-methyl)piperidine-4-carboxylate (11.5 g, 55 mmol) in tetrahydrofuran (100 mL)was added dropwise over 15 minutes. The reaction mixture was heated toreflux temperature and stirred for 4 hours. The mixture was cooled toambient temperature and ethyl acetate (100 mL) was added dropwise,followed by water (20 mL). The resulting suspension was filtered throughCelite®. The filtrate was concentrated in vacuo. Vacuum distillation (bp100° C., 0.1 mm Hg) afforded the product (6.15 g) : ¹ H-NMR:3.5 (d, 2H,J=7), 3.1 (d, 2H, J=7), 2.4 (d, 2H, J=7), 2.1-1.6 (m, 6H), 1.55-1.45 (m,3H), 0.95-0.85 (m, 1H), 0.55-0.45 (m, 2H), 0.25-0.15 (m, 2H); HRMS:Calcd for C₁₀ H₁₉ NO:169.1467; Found: 169.1467.

(2) Alternatively, this compound can be made as follows: Lithiumaluminum hydride (8.55 g, 0.225 mole) was added portionwise over 1 hourto a 0° C. solution of the ester from Step A above (47.6 g, 0.225 mole)in dry Et₂ O (500 mL). After 1.5 hours, the reaction was carefullyquenched with H₂ O (100 mL), then filtered through Celite(o and rinsedwith Et₂ O. The filtrate was diluted to 1 L total volume with Et₂ O, andthe phases were separated. The organic phase was extracted with brine,dried (MgSO₄), and concentrated in vacuo. The crude product wasdistilled, bp 108°-127° C. at 1.2 mm Hg, to yield the product as acolorless oil (29.3 g, 77%), which gave ¹ H-NMR and MS data as listedabove in Example 420 B (1).

C. 1-(Cyclopropylmethyl)-4-(4'-Fluorophenoxymethyl) piperidine

A solution of 4-fluorophenol (4.08 g, 36.4 mmol),1-(cyclopropylmethyl)-4-hydroxymethyl-piperidine (6.15 g, 36.4 mmol)from Step B (1) or (2), and triphenylphosphine (14.43 g, 55 mmol) inbenzene (100 mL) was stirred with ice-water bath cooling. Diethylazodicarboxylate (9.58 g, 8.7 mL, 55 mmol) was added dropwise viasyringe. The reaction mixture was heated to reflux and stirred for about72 hour. The mixture was cooled to ambient temperature and solvent wasremoved in vacuo. The residue was dissolved in ethyl acetate (200 mL),and the organic solution was washed twice with water (100 mL) then twicewith a 2N sodium hydroxide solution (100 mL). Drying over magnesiumsulfate, filtration and removal of solvent in vacuo gave a solid. Columnchromatography using a gradient elution system(chloroform:methanol::95:5 to 4:1) afforded the product 740 mg, 8%yield, mp 34°-36° C.) which gave ¹ H-NMR and MS data identical to thatfor the product from Example 1D.

The compounds of Table 13 may be prepared using the procedure describedfor Example 429, employing the appropriate phenol.

                  TABLE 13                                                        ______________________________________                                         ##STR31##                     (I)                                            Ex.          R              mp (°C.)                                   ______________________________________                                        429-C        4-F            34-36                                             430          4-NO.sub.2     68-70                                             431          4-CO.sub.2 CH.sub.3                                              432          4-CON(CH.sub.3).sub.2                                            433          4-CN           109-111 (a)                                       ______________________________________                                         Footnote for Table 13                                                         (a) See also Example 515                                                 

Example 434 and subsequent examples describe the preparation ofadditional compounds of formula (I) (where X=CO or CHOH).

EXAMPLE 434 Synthesis of1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine A.(1) 1-(4'-fluorophenyl)-2-(4"-pyridyl)ethanone

A solution of di-isopropylamine (4.44 g, 6.16 mL, 44 mmol) in anhydroustetrahydrofuran (50 mL) was cooled to about 0° C. with stirring in aflame-dried flask under a nitrogen atmosphere. A solution of n-butyllithium in hexane (2.5 M, 17.6 mL, 44 mmol) was added dropwise, then thereaction mixture was stirred at about 0° C. for about 15 minutes. Asolution of 4-picoline (3.92 g, 40 mmol) in anhydrous tetrahydrofuran(50 mL) was added dropwise, then the reaction mixture was stirred atabout 0° C. for about 15 minutes.

A solution of ethyl 4-fluorobenzoate (6.73 g, 5.87 mL, 40 mmol) intetrahydrofuran (100 mL) was stirred at about 0° C. under a nitrogenatmosphere. The pyridinemethyl lithium solution, prepared above wasadded dropwise via a canula. The reaction mixture was then stirred whilebeing warmed to ambient temperature for about 3 hours. The reactionmixture was then poured onto a 2N sodium hydroxide solution (200 mL) andextracted with ethyl acetate three times. The combined organic layerswere dried over magnesium sulfate, filtered and concentrated in vacuo.

Column chromatography of the residue with ethyl acetate gave theproduct, a yellow solid (1.0 g, R_(f) =0.2) : mp 90°-93° C.; ¹ H-NMR:8.65-8.5 (m, 2H) , 8.05 (dd, 2H, J=8,6), 7.25-7.1 (m, 4H), 4.3 (s, 2H);MS:215; IR (KBr): 1684(s), 1596(s), 1505(m), 1417(m).

The column was eluted with ethyl acetate-methanol (4:1) to give, afterremoval of solvent in vacuo, a glassy solid, 4-fluorophenylbis-(4-pyridylmethyl) methanol (1.1 g) :mp 35°-36° C.; ¹ H-NMR: 8.2 (d,4H, J=6), 7.25 (dd, 2H, J=8,6), 7.0 (dd, 2H, J=7), 6.85 (d, 2H, J=6),3.8-3.6 (m, 1H), 3.2 (q, 4H, J=10); MS:308; IR(KBr):3420 (br, s), 2928(m), 1603 (s), 1560 (m), 1510 (s), 1419 (s); Anal.: Calcd for C₁₉ H₁₇FNO.0.5.H₂ O: C, 71.91, H, 5.72, N, 8.83; Found: C, 71.75, 72.00, H,5.60, 5.64, N, 8.44, 8.61.

Alternatively, Step 434 A(2) may be used to make an appropriateintermediate.

A. (2) 1-(4'-Fluorophenyl)-2-(4'-pyridyl)ethanone

A solution of sodium bis(trimethylsilylamide) in tetrahydrofuran (1 M,400 mL, 0.4 mol) was cooled to about 0° C. with stirring under anitrogen atmosphere. A solution of 4-picoline (37.25 g, 38.9 mL, 0.4mol) in anhydrous tetrahydrofuran (560 mL) was added dropwise over 30minutes. The reaction mixture was stirred at 0°-10° C. for 30 minutes.

A solution of ethyl 4-fluorobenzoate (33.6 g, 29.3 mL, 0.2 mol) inanhydrous tetrahydrofuran (400 mL) was cooled to about 0° C. withstirring under a nitrogen atmosphere. The above solution of4-pyridinemethyl sodium was added dropwise via an additional funnel suchthat the internal temperature did not exceed 15° C. The reaction mixturewas then stirred at ambient temperature for about 3 hours. The reactionmixture was poured onto water (1 L) and extracted three times with ethylacetate. The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo. Vacuum distillation (bp 140° C., 0.1mm Hg) gave the product (25.3 g), which solidified on cooling and whichwas identical in all respects to the product from Example 434 A(1).

B. 1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)pyridiniumbromide

A mixture of 1-(4'-fluorophenyl)-2-(4'-pyridyl)ethanone from Step A(1)or A(2) above (5 g, 23.3 mmol) and bromomethyl cyclopropane (18.8 g,13.5 mL, 140 mmol) was stirred at reflux temperature under a nitrogenatmosphere for about 1 hour. A pale yellow solid formed upon cooling toambient temperature. Filtration and trituration with copious amounts ofether afforded a pale yellow solid:¹ H-NMR: 9.45 (d, 2H, J=6), 8.35-8.0(m, 4H), 7.2 (br t, 2H, J=7), 5.0-4.8 (m, 4H), 1.65-1.4 (m, 1H) , 0.85-0. 65 (m, 4H)

C. 1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine

Platinum dioxide (1 g) was suspended in degassed ethanol (100 mL) andthis suspension was stirred under a hydrogen atmosphere until hydrogenuptake ceased. A solution of1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)pyridiniumbromide from Step B above, (7.9 g) in degassed ethanol (200 mL) wasadded and the mixture was stirred under a hydrogen atmosphere. After thetheoretical amount of hydrogen had been taken up, the suspension wasfiltered through Celite®. Solvent was removed in vacuo to give theproduct as its hydrobromide salt, a white solid.

This solid was dissolved in water; the solution was basified with a 2Nsodium hydroxide solution, then extracted with chloroform three times.The combined organic layers were dried over magnesium sulfate andfiltered. Solvent was removed in vacuo. Column chromatography(chloroform:methanol::9:1) gave the product, a pale yellow solid (R_(f)=0.25, 2.83 g): mp 73°-75° C.; IR (KBr) : 3072 (w) , 3006 (w) , 2995 (w), 2943 (s) , 2903 (s), 2840 (w), 2806 (w), 1679 (s), 1594 (s), 1504 (s),1462 (s), 1448 (w), 1427 (w), 1410 (s); ¹ H-NMR: 8.0 (dd, 2H, J=8,6),7.15 (br t, 2H, J=8), 3.1 (br d, 2H, J=9), 2.9 (d, 2H, J=7), 2.35 (d,2H, J=7), 2.1-1.6 (m, 6H), 1.55-1.35 (m, 2H), 1.0-0.8 (m, 1H), 0.65-0.4(m, 2H), 0.25-0.0 (m, 2H); MS:275; Anal.: Calcd for C₁₇ H₂₂ FNO.0.25.H₂O: C, 72.96, H, 8.10, N, 5.00, F, 6.78; Found: C, 73.16, 72.99, H, 8.10,8.06, N, 5.11, 5.13, F, 6.58, 6.52.

The compounds of Table 14 may be prepared using, in sequence, theprocedures described in Examples 434 A(1) or A(2), B and C starting withthe appropriate benzoate ester.

                  TABLE 14                                                        ______________________________________                                         ##STR32##                                                                    Ex.      R             Salt       mp (°C.)                             ______________________________________                                        434      4-F                      73-75                                       435      4-Cl          HBr        154-155 (a)                                 436      4-Br                                                                 437      4-I                                                                  438      H                                                                    439      4-N(CH.sub.3).sub.2      104-106 (b)                                 440      4-NHCOCH.sub.3                                                       441      4-NH.sub.2                                                           442      4-OCH.sub.3   HBr        167-168 (c)                                 443      4-OTBDMS                 (d)                                         444      4-OC.sub.2 H.sub.5                                                   445      4-SCH.sub.3                                                          446      4-SC.sub.2 H.sub.5                                                   447      4-CH.sub.2 NH.sub.2                                                  448      3,5-(CF.sub.3).sub.2                                                 449      4-CH.sub.3                                                           450      4-C.sub.2 H.sub.5                                                    451      4-CF.sub.3               35-36 (e)                                   452      3-Cl                                                                 453      2-Cl                                                                 454      3-Br                                                                 455      2-Br                                                                 456      3-I                                                                  457      2-I                                                                  458      3-N(CH.sub.3).sub.2                                                  459      3-NHCOCH.sub.3                                                       460      3-NH.sub.2                                                           461      3-OCH.sub.3                                                          462      3-OTBDMS                                                             463      3-OC.sub.2 H.sub.5                                                   464      3-SCH.sub.3                                                          465      3-CH.sub.2 NH.sub.2                                                  466      3-CH.sub.2 N(CH.sub.3).sub.2                                         467      3-CF.sub.3                                                           468      2-Cl-5-Br                                                            469      3-Br-4-CH.sub.3                                                      470      4-t-C.sub.4 H.sub.9 O                                                471      4-t-C.sub.4 H.sub.9                                                                         HBr        142-144 (f)                                 472      2-Cl-4-F                                                             473      3-Cl-4-F                                                             474      3-Cl-4-OTBDMS                                                        475      4-Cl-2-OCH.sub.3                                                     476      3-Cl-4-CH.sub.3                                                      477      2-Cl-5(CH.sub.3 S)                                                   478      2-Cl-4-(NH.sub.2)                                                    479      4-Cl-3-NH.sub.2                                                      480      3,5-Br.sub.2 -4-OTBDMS                                               481      3,4-Cl.sub.2                                                         482      2,4-Cl.sub.2                                                         483      3,5-Cl.sub.2                                                         484      2,5-Cl.sub.2                                                         485      3,5-Cl.sub.2 -4-OTBDMS                                               486      3,4-(OC.sub.2 H.sub.5).sub.2                                         487      3,4-(OCH.sub.3).sub.2                                                488      3,4-(OCH.sub.3).sub.2                                                489      4-(C.sub.2 H.sub.5).sub.2 N                                          490      3,4-F.sub.2                                                          491      2,4-F.sub.2                                                          492      3,5-F.sub.2                                                          493      3,4-(CH.sub.3).sub.2                                                 494      3,5-(CH.sub.3).sub.2                                                 495      3,5-(NH.sub.2).sub.2                                                 496      3-CH.sub.3 O-4NH.sub.2                                               497      F.sub.5                                                              498      Cl.sub.5                                                             499      2,3,4,5-F.sub.4                                                      500      2,3,5-Cl.sub.2                                                       501      2,3,4-F.sub.3                                                        502      2,4,5-F.sub.3                                                        503      4-C.sub.6 H.sub.5                                                                           HBr        233-234 (g)                                 ______________________________________                                         Footnotes for Table 14                                                        (a) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 7.88(d, 2H, J=8), 7.45(d, 2H, J=8),     3.77-3.68(m, 2H), 3.02(d, 2H, J=7), 2.90(d, 2H, J=8), 2.85-2.71(m, 2H),       2.40-1.97(m, 5H), 1.59(br m, 1H), 1.40-1.30(m, 1H), 0.85-0.78(m, 2H),         0.48-0.40(m, 2H); Anal.: Calcd for C.sub.17 H.sub.22 ClNO.HBr: C, 54.78,      H, 6.22, N, 3.76; Found: C, 54.50, H, 6.21, N, 3.85.                          (b) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 7.9(d, 2H, J=9), 6.65(d, 2H, J=9),      3.2(br d, 2H, J=11), 3.1(s, 6H), 2.85(d, 2H, J=7), 2.4(d, 2H, J=7),           2.3-1.95(m, 4H), 1.9-1.7(m, 2H), 1.7-1.45(m, 2H), 1.1-0.9(m, 1H),             0.7-0.6(m, 2H), 0.3-0.1(m, 2H), HRMS: Calcd for C.sub.19 H.sub.28 N.sub.2     O: 300.2202; Found: 300.2218; Anal.: Calcd for C.sub.19 H.sub.28 N.sub.2      O.0.5.H.sub.2 O: C, 73.75, H, 9.28, N, 9.05; Found: C, 73.22, H, 9.05, N,     8.87.                                                                         (c) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 7.91(d, 2H, J=8), 6.94(d, 2H, J=8),     3.91(s, 3H), 3.76-3.68(m, 2H), 2.95(d, 2H, J=7), 2.90(d, 2H, J=7),            2.85-2.75(m, 2H), 2.40-2.15(m, 3H), 2.05-1.95(m, 2H), 1.60(br m, 1H),         1.40-1.31(m, 1H), 0.84-0.77(m, 2H), 0.50-0.43(m, 2H); Anal.: Calcd for        C.sub.18 H.sub.25 NO.sub.2.HBr: C, 58.70, H, 7.12, N, 3.80; Found: C,         58.75, 58.54, H, 7.19, 7,14, N, 3.81, 3.81.                                   (d) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 7.85(br d, 2H, J=8), 6.85(br d, 2H,     J=8), 3.05(br d, 2H, J=10), 2.85(d, 2H, J=7), 2.25(d, 2H, J=7), 2.1(br t,     3H, J=7), 1.85-1.7(m, 2H), 1.5-1.3(m, 2H), 1.0(s, 9H), 0.95-0.8(m, 2H),       0.55-0.45(m, 2H), 0.25(s, 6H), 0.15-0.05(m, 2H); HRMS: Calcd for C.sub.23     H.sub.37 NO.sub.2 Si: 387.2594; Found: 387.2591.                              (e) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 8.05(d, 2H, J=8), 7.75(d, 2H, J=8),     3.1(br d, 2H, J=10), 2.95(d, 2H, J=7), 2.3(d, 2H, J=7), 2.2-1.95(m, 3H),      1.9-1.7(m, 2H), 2.6-2.35(m, 2H), 1.0-0.8(m, 1H), 0.6-0.45(m, 2H),             0.2-0.05(m, 2H), HRMS: Calcd for C.sub.18 H.sub.22 F.sub.3 NO: 325.1676;      Found: 325.1652; Anal.: Calcd for C.sub.18 H.sub.22 F.sub.2                   NO.0.25.H.sub.2 O: C, 65.54, H, 6.87, N, 4.24, F, 17.27; Found: C, 65.57,     65.52, H, 6.89, 6.89, N, 4.31, 4.36, F, 17.34.                                (f) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 7.89(d, 2H, J=8), 7.49(d, 2H, J=8),     3.77-3.69(m, 2H), 3.02(d, 2H, J=6), 2.90(d, 2H, J=8), 2.84-1.30(m, 9H),       1.35(s, 9H), 0,85-0.78(m, 2H), 0.48-0.41(m, 2H), HRMS: Calcd for C.sub.21     H.sub.21 NO: 313.2406; Found: 313.2405; Anal.: Calcd for C.sub.21 H.sub.3     NO.HBr.0.5 H.sub.2 O: C, 62.52, H, 8.25, N, 3.47; Found: C, 62.70, 62.47,     H, 8.00, 7.94, H, 3.34, 3.33.                                                 (g) .sup. 1 HNMR(CDCl.sub.3, 300 MHz): 8.03(d, 2H, J=8), 7.70(d, 2H, J=8)     7.65-7.40(m, 5H), 3.78-3.69(m, 2H), 3.08(d, 2H, J=7), 2.90(d, 2H, J=8),       2.87-2.75(m, 2H), 2.43-1.98(m, 5H), 1.58(br m, 1H), 1.43-1.32(m, 1H),         0.95-0.87(m, 2H), 0.49-0.41(m, 2H); Anal.: Calcd for C.sub.23 H.sub.25        NO.HBr: C, 66.66, H, 6.81, N, 3.38; Found: C, 66.23, 66.22, H, 6.86, N,       7.08; N, 3.41, 3.42.                                                     

EXAMPLE 5041-(Cyclopropylmethyl)-4-2'-(4"-Fluorophenyl)-2-oxoethyl)-piperidine,hydrobromide salt

A mixture of1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2-oxoethyl)piperidine(24.1 g, 87.6 mmol), a hydrobromic acid solution (0.4 M, 62 ml) andethanol (50 mL) was stirred with gentle heating until all soliddissolved. Solvent was removed in vacuo with gentle heating to give awhite solid. The solid was suspended in a 2-propanol and mixed; againsolvent was removed in vacuo with gentle heating to give a white solid.Trituration with ether and filtration gave the product. Drying in vacuoat about 60° C. in a drying oven gave a white powder. (25.9 g): mp141°-143° C.; IR (KBr) 3067 (w), 3038 (w), 2986 (m), 2939 (s), 2921 (s),2702 (s), 2645 (s), 2592 (s), 2567 (s), 2520 (s), 1683 (s), 1601 (s),1509 (s), 1470 (m), 1459 (s), 1436 (s), 1412 (s); ¹ H-NMR (DMSO-d₆):9.5-9.2 (m, 1H), 8.2-8.0 (br t, 2H, J=7), 7.4 (br t, 2H, J=7), 3.6-2.8(m, 8H), 2.25-1.4 (m, 4H), 1.25-1.0 (m, 1H), 0.7-0.5 (m, 2H), 0.45-0.3(m, 2H); Anal.: Calcd for C₁₇ H₂₂ FNO.HBr: C, 57.31, H, 6.51, N, 3.93,F, 5.33, Br, 22.43; Found: C, 57.57, H, 6.65, N, 3.86, F, 5.15, Br,22.16.

The compounds of Table 15 may be prepared by the procedure for Example504 using the appropriate acid.

                  TABLE 15                                                        ______________________________________                                         ##STR33##                     (I)                                            Ex.       R         Salt        mp (°C.)                               ______________________________________                                        504       4F        HBr         141-143                                       505       4-CF.sub.3                                                                              HCl         140-142 (a)                                   506       4-N(CH.sub.3).sub.2                                                                     HBr         113-115 (b)                                   ______________________________________                                         Footnotes for Table 15                                                        (a) Anal.: Calcd for C.sub.18 H.sub.22 F.sub.3 NO.HCl.0.5H.sub.2 O: C,        58.29, H, 6.52, N, 3.77, F, 15.27, Cl, 9.56; Found: C, 58.49, 58.22, H,       6.34, 6.33, N, 3.84, 3.80, F, 15.24, 15.32, Cl, 9.50, 9.28.                   (b) Anal.: Calcd for C.sub.19 H.sub.28 N.sub.2 O.2HBr.0.5H.sub.2 O: C,        48.42, H, 6.63, N, 5.94, Br, 33.91; Found: C, 48.83, 48.73, H, 6.89, 6.76     N, 5.65, 5.44, Br, 33.10, 33.27.                                         

EXAMPLE 5071-(Cyclopropylmethyl)-4-(2'-(4"-hydroxyphenyl)-2'-oxoethyl)piperidine,hydrochloride salt

1-(Cyclopropylmethyl)-4-(2'-(4"-t-butyldimethylsilyloxyphenyl)-2'-oxoethyl)piperidine(from Example 443 above) (250 mg, 1.02 mmol) was reacted with a solutionof tetra-n-butylammonium fluoride in tetrahydrofuran (1 M, 3 mL, 3 mmol)for about 14.5 hours. Solvent was removed in vacuo. The residue wasdissolved in water; a 1N hydrochloric acid solution was added untilpH=7. Three extractions with ethyl acetate, drying over magnesiumsulfate, filtration and concentration in vacuo gave a light brown oil.

The oil was dissolved in ether-ethanol (5 mL, 1:1 (v/v)). A solution ofhydrogen chloride in ether (1 M, 5 mL, 5 mmol) was added with stirring.Solvent was removed in vacuo; the residue was triturated with acetoneand filtered. Drying in vacuo gave a white solid (25 mg) : mp 209°-211°C.; NMR (DMSO-d₆, 300 MHz) 10.4 (s, 1H), 7.9 (d, 2H, J=8), 6.85 (d, 2H,J=B), 3.55-3.45 (m, 1H), 3.0-2.8 (m, 1H), 1.95-1.85 (m, 2H), 1.7-1.5 (m,2H), 1.15-1.0 (m, 1H), 0.7-0.6 (m, 2H), 0.45-0.35 (m, 2H); HRMS: Calcdfor C₁₇ H₂₃ NO₂ :273.1729; Found: 273.1727.

EXAMPLE 508 1-(Cyclopropylmethyl)-4-(4'-cyanophenoxymethyl)piperidine

Sodium hydride (50% in oil, 0.48 g, 10 mmol) was washed with hexanestwice (decanting the solvent each time) and suspended inN,N-dimethylformamide (20 mL) with stirring under a nitrogen atmosphere.A solution of 1-(cyclopropylmethyl)-4-(hydroxy-methyl)piperidine(Example 429B) (1.6 g, 9.5 mmol) in N,N-dimethylformamide (10 mL) wasadded dropwise. Gas evolution occurred. 4-Fluorobenzonitrile (1.21 g, 10mmol) was added, then the reaction mixture was stirred at 100° C. for 17hours. Water was added. The solvent was distilled in vacuo. The residuewas taken up in water, basified with a 1N sodium hydroxide solution andextracted three times with ethyl acetate. The combined organic layerswere dried over MgSO₄ and filtered. Solvent was removed in vacuo to givea brown oil.

Column chromatography (chloroform: methanol::9:1) gave a brown oil,after removal of solvent in vacuo. The oil was crystallized fromether-hexanes and filtered. Drying in vacuo afforded the product, awhite powder (1.23 g) : mp 109°-111° C.; IR (KBr) 3074 (w), 2997 (m),2962 (w), 2939 (s), 2918 (s), 2883 (s), 2826 (s), 2779 (m), 2232 (s),1607 (s), 1574 (m), 1511 (s); NMR CDCl₃, 300 MHz): 7.75 (d, 2H, J=8),6.9 (d, 2H, J=8), 3.85 (d, 2H, J=7), 3.1 (br d, 2H, J=10), 2.25 (d, 2H,J=7), 2.0 (td, 2H, J=8), 1.9-1.75 (m, 3H), 1.5-1.35 (m, 2H), 0.9-0.8 (m,1H), 0.55-0.45 (m 2, H), 0.15-0.05 (m, 2H); HRMS: Calcd for C₁₇ H₂₂ N₂O: 270.1732; Found: 270.1727; Anal.: Calcd for C₁₇ H₂₂ N₂ O: C, 75.52,H, 8.20, N, 10.36; Found: C, 75.36, H, 8.35, N, 10.27.

The compounds in Table 16 may be prepared by the method described inExamples 1, 429 or 508 using the appropriate benzene derivative.

                  TABLE 16                                                        ______________________________________                                         ##STR34##                     (I)                                            Ex.  R             X       p    Salt   mp (°C.)                        ______________________________________                                        509  4-F           S       1           (a)                                    510  4-F           NMe     1                                                  511  4-F           CHOH    1           114-116 (b)                            512  4-NO.sub.2    O       1           68-70 (c)                              513  4-F           NH      1                                                  514  1-tetrazole   O       1                                                  515  4-CN          O       1           109-111 (d)                            516  4-COCH.sub.3  O       1           41-43 (e)                              517  4-SO.sub.2 (OCH.sub.2 C.sub.6 H.sub.5)                                                      O       1                                                  518  4-CO.sub.2 CH.sub.2 Ph                                                                      O       1                                                  519  4-CHO         O       1                                                  520  4-SO.sub.2 N(CH.sub.3).sub.2                                                                O       1           118-119 (f)                            521  4-F           O       3                                                  522  4-F           CO      0                                                  523  4-F           SO      1           (g)                                    524  4-F           SO.sub.2                                                                              1           73 (h)                                 525  4-F           CO      2    HBr    108-109 (i)                            526  4-F           O       2           (j)                                    527  4-F           O       2    fumarate                                                                             124-126 (k)                            ______________________________________                                         Footnotes for Table 16                                                        (a) .sup.1 HNMR(CDCl.sub.3, 200 MHz): 7.3(dd, 2H, J=8, 6), 7.0(t, 2H,         J=8), 3.1(br d, 2H, J=10), 2.8(d, 2H, J=7), 2.15(d, 2H, J=7), 2.0-1.8(m,      4H), 1.6-1.3(m, 3H), 0.95-0.8(m, 1H), 0.6-0.45(m, 2H), 0.15-0.05(m, 2H);      HRMS: Calcd for C.sub.16 H.sub.22 FNS: 279.1457; Found: 279.1460.             (b) Anal.: Calcd for C.sub.17 H.sub.24 FNO: C, 73.61, H, 8.72, N, 5.05, F     6.84; Found: C, 72.64, 72.96, H, 8.77, 8.61, N, 5.00, 4.92, F, 6.86.          (c) Anal.: Calcd for C.sub.16 H.sub.22 N.sub.2 O.sub.3.0.75H.sub.2 O: C,      63.26, H, 7.74, N, 9.22; Found: C, 63.14, 63.10, H, 7.40, 7.39, N, 9.35,      9.28.                                                                         (d) Anal.: Calcd for C.sub.17 H.sub.24 N.sub.2 O: C, 75.52, H, 8.20, N,       10.36; Found: C, 75.36 H, 8.35, N, 10.27. (See also Example 433).             (e) Anal.: Calcd for C.sub.18 H.sub.25 NO.sub.2 : C, 75.23, H, 8.77, N,       4.87; Found: C, 75.10, H, 8.87, N, 4.76.                                      (f) Anal.: Calcd for C.sub.18 H.sub.22 N.sub.2 O.sub.3 S: C, 61.33, H,        8.01, N, 7.95, S, 9.10; Found: C, 60.64, 60.64, H, 7.98, 7.94, N, 7.63,       7.64, S, 9.03.                                                                (g) Anal.: Calcd for C.sub.16 H.sub.22 FNO.sub.2 S: C, 61.71, H, 7.12, N,     4.49, F, 6.10, S, 10.30; Found: C, 61.57, H, 7.26, N, 4.39, F, 6.40, S,       10.36.                                                                        (h) .sup.1 HNMR(CDCl.sub.3, 200 MHz): 7.65(dd, 2H, J=7, 2), 7.25(dd, 2H,      J=8, 2), 3.1(br t, 2H, J=9), 2.85(dd, 1H, J=10, 2), 2.5(dd, 1H, J=10, 8),     2.4-2.2(m, 2H), 2.15-1.9(m, 5H), 1.8-1.7(m, 1H), 1.55-1.4(m, 2H),             0.9-0.8(m, 1H); 0.6-0.45(m, 2H), 0.15-0.05(m, 2H); HRMS: Calcd for            C.sub.16 H.sub.22 FNOS: 295.1406; Found: 295.1409.                            (i) Anal.: Calcd for C.sub.18 H.sub.24 FNO.HBR: C, 58.38, H, 6.53, N,         3.78, F, 5.13, Br, 21.57; C, 58.13, 58.35, H, 6.51, 6.38, N, 3.70, 3.61,      F, 4.95, 4.93, Br, 21.59.                                                     (j) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 6.9(br t, 2H, J=8), 6.75(dd, 2H,        J=8, 6), 3.7(d, 2H, J=7), 2.9(br d, 2H, J=9), 2.5-2.35(m, 2H), 2.0-1.85(m     2H), 1.85-1.65(m, 3H), 1.5-1.3(m, 4H), 0.7-0.5(m, 1H), 0.45-0.3(m, 2H);       0.1-0.0(m, 2H); HRMS: Calcd for C.sub.17 H.sub.24 FNO: 277.1842; Found:       277.1837.                                                                     (k) Anal.: Calcd for C.sub.17 H.sub.24 FNO.C.sub.4 H.sub.4 O.sub.4 : C,       64.11, H, 7.17, N, 3.56, F, 4.82; Found: C, 64.05, 64.30, H, 7.30, 7.41,      N, 3.89, 3.90, F, 4.83, 4.85.                                            

The compounds in Table 17 may be prepared by the method described inExample 1C using the appropriate hydroxy aromatic compound.

                  TABLE 17                                                        ______________________________________                                         ##STR35##                     (I)                                            Ex.     R             X     n      mp (°C.)                            ______________________________________                                        528     4-piperidinyl O     1                                                 529     4-C.sub.6 H.sub.5                                                                           O     1                                                 530     4-C.sub.6 H.sub.5 O                                                                         O     1      62-63 (a)                                  531     4-C.sub.6 H.sub.5 S                                                                         O     1                                                 532     4-(4'-FC.sub.6 H.sub.4)                                                                     O     1      81-83 (b)                                  533     4-(4'-CH.sub.3 OC.sub.6 H.sub.4)                                                            O     1      122-123 (c)                                534     4-(4'-CH.sub.3 C.sub.6 H.sub.4)                                                             O     1                                                 535     4-(4'-CH.sub.3 SC.sub.6 H.sub.4)                                                            O     1                                                 536     4-(4'-CF.sub.3 C.sub.6 H.sub.4)                                                             O     1                                                 537     4-F           O     0                                                 ______________________________________                                         Footnotes for Table 17                                                        (a) Anal.: Calcd for C.sub.22 H.sub.27 NO.sub.2 : C, 78.30, H, 8.06, N,       4.15; Found: C, 78.20, H, 8.12, N, 4.04.                                      (b) Anal.: Calcd for C.sub.22 H.sub.26 FNO: C, 77.84, H, 7.72, N, 4.13, F     5.60; Found: C, 77.71, 77.71, H, 7.78, 7.78, N, 3.93, 3.93, F, 3.77, 3.60     (c) Anal.: Calcd for C.sub.23 H.sub.29 NO.sub.2.0.5H.sub.2 O: C, 76.62, H     8.39, N, 3.88; Found: C, 76.83, 76.86, H, 8.20, 8.17, N, 3.60, 3.58.     

The compounds in Table 18 may be prepared by the methods described inExample 508 or 410, using the appropriate starting materials.

                  TABLE 18                                                        ______________________________________                                         ##STR36##                                                                    Ex.       Ar        HX          mp (°C.)                               ______________________________________                                        538       2-pyrimidyl           (a)                                           539       2-pyrimidyl                                                                             HCl         151-152 (b)                                   540       2-pyridyl             (c)                                           541       2-pyridyl HCl         176-178 (d)                                   ______________________________________                                         Footnotes for Table 18                                                        (a) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 8.45-8.35(m, 2H), 6.85-6.8(m, 1H),      4.1(d, 2H, J=7), 3.05(br d, 2H, J=10), 2.2(d, 2H, J=7), 2.0-1.7(m, 5H),       1.45-1.3(m, 2H), 0.9-0.75(m, 2H), 0.1-0.0(m, 2H).                             (b) Anal.: Calcd for C.sub.14 H.sub.21 N.sub.3 O.1.3HCl: C, 57.05, H,         7.62, N, 14.26, Cl, 15.64; Found: C, 56.18, 56.34, H, 7.51, 7.65, N,          13.95, 14.05, Cl, 15.05, 15.25.                                               (c) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 8.05-8.0(m, 1H), 7.15-7.35(m, 1H),      6.8-6.7(m, 1H), 6.65-6.55(m, 1H), 4.05(d, 2H, J=7), 3.05(br d, 2H, J=10),     2.2(d, 2H, J=7), 1.9(br t, 2H, J=9), 1.8-1.6(m, 3H), 1.5-1.3(m, 2H),          0.9-0.7(m, 1H); 0.5-0.35(m, 2H), 0.1-0.0(m, 2H); MS: 246.                     (d) Anal.: Calcd for C.sub.15 H.sub.22 N.sub.2 O.1.5HCl: C, 56.52, H,         7.43, N, 8.78, Cl, 16.68; Found: C, 56.37, 56.18, H, 7.77, 7.76, N, 8.61,     8.44, Cl, 19.76, 19.66.                                                  

EXAMPLE 5421-(Cyclopropylmethyl)-4-(2'-(4"-cyanophenyl)-2'-oxoethyl)piperidine

A mixture of sodium cyanide (4.9 g, 100 mmol) and1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxo ethyl)piperidine(Example 434, 1.0 g, 3.6 mmol) in N,N-dimethylformamide (50 mL) wasstirred at 120° C. for 26 h. The excess solvent was distilled in vacuo;the residue was dissolved in water and extracted three times with ethylacetate. The combined organic layers were washed with water twice, driedover anhydrous magnesium sulfate and filtered. Solvent was removed invacuo to give an oil.

Column chromatography (CHCl₃ : MeOH::9:1) afforded the product, a solid(0.68 g. 67% yield): mp 107°-108° C.; Anal.: Calcd for C₁₈ H₂₂ N₂O.0.25H₂ O: C, 75.38, H, 7.90, N, 9.76; Found: C, 75.13, 74.97, H, 7.87,7.96, N, 9.65, 9.52.

EXAMPLE 5431-(Cyclopropylmethyl)-4-(2'-(4"-aminophenyl)-2'-oxoethyl)piperidine

Following the procedure of Example 542, sodium azide (6.5 g, 100 mmol)was reacted with the product of Example 434 (1.0 g, 3.6 mmol) to affordthe title compound, a solid (0.35 g): mp 140-146 (dec); MS:272; Anal.:Calcd for C₁₇ H₂₂ N₂ O.0.75H₂ O: C, 71.42, H, 8.99, N, 9.80; Found: C,71.06, 71.03, H, 8.58, 8.54, N, 9.98, 9.99.

EXAMPLE 5441-(Cyclopropylmethyl)-4-(4'-methylsulfonylphenoxymethyl)piperidine

A mixture of a 1N NAOH solution (10 mL) and 17(cyclopropylmethyl)-4-(4'-methylthiophenoxymethyl)piperidine,hydrochloride salt (Example 420, 0.5 g, 1.5 mmol) was stirred for 15 minand then extracted three times with ethyl acetate. The combined organicextracts were dried over anhydrous magnesium sulfate and filtered.Solvent was removed in vacuo. The residue was taken up in a mixture ofmethanol (10 mL) and water (10 mL). Sodium periodate (2.13 g, 10 mmol)was added; the resulting suspension was stirred for 22 h. The reactionmixture was diluted with 250 mL water, basified with 1N NAOH solutionand extracted three times with ethyl acetate. The combined organiclayers were dried over magnesium sulfate and filtered. Solvent wasremoved in vacuo.

Column chromatography (CHCl₃ :MeOH::9:1) of the residue afforded thetitle compound, a solid (0.29 g): mp 134°-135° C.; ¹ H-NMR (CDCl₃, 300MHz) : 7.85 (d, 2H, J=8), 7.0 (d, 2H, J=8), 3.9 (d, 2H, J=7), 3.15 (brd, 2H, J=10), 3.05 (s, 3H), 2.3 (d, 2H, J=7), 2.1 (br t, 2H, J=7),1.95-1.8 (m, 3H), 1.6-1.4 (m, 2H), 0.95-0.85 (m, 1H), 0.6-0.5 (m, 2H),0.2-0.1 (m, 2H); HRMS: Calcd for C₁₇ H₂₅ NO₃ S: 323.1555; Found:323.1554.

EXAMPLES 545 AND 5461-(Cyclopropylmethyl)-4-(4'-fluorophenylsulfonylmethyl)piperidine(Example 545) and 1- (cyclopropylmethyl) -4-(4'-fluorophenyl-sulfinylmethyl) piperidine (Example 546)

1-(Cyclopropylmethyl)-4-(4'-fluorophenylthiomethyl)piperidine,hydrobromide salt (Example 509, hydrobromide salt, 1.0 g) was treatedwith a 1N NAOH solution (50 mL); the mixture was extracted with ethylacetate three times. The organic solution was dried over magnesiumsulfate and filtered. Solvent was removed in vacuo.

The residue was reacted with sodium periodate (7.7 g, 36 mmol) inmethanol (30 mL) and water (30 mL for 21.5 h). The reaction mixture wasdiluted with water (500 mL), basified with a 1N NAOH solution andextracted three times with ethyl acetate. The combined organic layerswere dried over magnesium sulfate and filtered. Solvent was removed invacuo.

Column chromatography (CHCl₃ :MeOH::9:1) gave two products:

(1) (Cyclopropylmethyl)-4-(4'-fluorophenylsulfonylmethyl)piperidine(Example 545) R_(f) =0.3, 367 mg): mp 73° C.; ¹ H-NMR (CDCl₃, 200 MHz) :7. 95 (dd, 2H, J=7, 2) , 7.25 (dd, 2H, J=8,2), 3.1-2.95 (m, 2H), 3.05(d, 2H, J=7), 2.25 (d, 2H, J=7), 2.1-1.85 (m, 4H), 1.55-1.4 (m, 2H),0.9-0.8 (m, 1H), 0.55-0.45 (m, 2H), 0.15-0.05 (m, 2H); Anal.: Calcd forC₁₆ H₂₂ FNO₂ S: C, 61.71, H, 7.12, N, 4.49, F, 6.10, S, 10.30; Found: C,61.57, H, 7.26, N, 9.39, F, 6.40, S, 10.36;

(2) 1-(cyclopropylmethyl)-4-(4'-fluorophenylsulfinylmethyl)piperidine(Example 546, R_(f) =0.17, 90 mg): ¹ H-NMR (CDCl₃, 200 MHz): 7.65, (dd,2H, J=7,2), 7.25 (dd, 2H, J=8,2), 3.1 (br t, 2H, J=9), 2.85 (dd, 1H,J=10,2), 2.5 (dd, 1H, J=10,8), 2.4-2.2 (m, 2H), 2.15-1.9 (m, 5H),1.8-1.7 (m, 1H), 1.55-1.4 (m, 2H), 0.9-0.8 (m, 1H), 0.6-0.45 (m, 2H),0.15-0.05 (m, 2H); HRMS: Calcd for C₁₆ H₂₂ FNOS: 295.1406; Found:295.1409.

EXAMPLE 5471-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-phenyl-2'-hydroxyethyl)piperidine

1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine(Example 429, 1.0 g, 3.6 mmol) was mixed with dry tetrahydrofuran (10mL). A solution of phenyl magnesium bromide in ether (3.0 M, 3 mL, 9mmol) was added with stirring. The reaction mixture was stirred for 24h; poured onto a saturated NH₄ Cl solution and extracted with ethylacetate three times. The combined organic layers were dried overmagnesium sulfate and filtered. Solvent was removed in vacuo.Trituration with ether-hexanes (1:9) and filtration afforded the titlecompound, a solid, which was dried in vacuo (0.9 g). mp 115°-116° C.;Anal. : Calcd for C₂₃ H₂₈ FNO: C, 77.36, H, 7.90, N, 3.92, F, 5.32;Found: C, 77.47, 77.41, H, 8.00, 7.92, N, 3.42, 3.52, F, 5.09.

EXAMPLE 548 1-(Cyclopropylmethyl)-4-(2',2'-bis(4"-Fluorophenyl)-2-hydroxyethyl)piperidine

Following the procedure described for Example 547, the compound ofExample 429 (1.0 g, 3.6 mmol) was reacted a solution of4-fluorophenylmagnesium bromide in tetrahydrofuran (1.0 M, 9 mL, 9 mmol)to give the title compound, a solid (1.1 g) : mp 119°-121° C.; Anal. :Calcd for C₂₃ H₂₇ F₂ NO.0.5H₂ O: C, 72.60, H, 7.41, N, 3.68, F, 9.99;Found: C, 72.89, 72.84, H, 7.14, 7.21, N, 3.29, 3.24, F, 9.82, 9.67.

EXAMPLE 5491-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxo-1'-benzylethyl)piperidine

A solution of the compound of Example 429 (1.0 g, 3.6 mmol) in drytetrahydrofuran (25 mL) was stirred at 0° C. A solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (1 M, 4 mL, 4 mmol) wasadded and stirring was continued for 40 min. Benzyl chloride (0.51 g,0.46 mL, 4 mmol) was added; the reaction mixture was heated to refluxtemperature and stirred for 23 h. The reaction mixture was cooled toambient temperature, poured onto water, basified with a 1N NAOH solutionand extracted with ethyl acetate three times. The combined organiclayers were dried over magnesium sulfate, filtered and concentrated invacuo. Column chromatography (CHCl₃ :MeOH::9:1) gave the title compound(455 mg), a yellow oil: ¹ H-NMR (CDCl₃, 200 MHz): 7.7 (dd, 2H, J=8,6),7.2-7.0 (m, 5H), 7.0 (t, 2H, J=8), 3.65-3.55 (m, 1H), 3.2-2.9 (m, 4H),2.25 (d, 2H, J=7), 2.0-1.7 (m, 4H), 1.65-1.4 (m, 3H), 0.9-0.75 (m, 1H),0.55-0.45 (m, 2H), 0.15-0.05 (m, 2H); HRMS: Calcd for C₂₄ H₂₈ FNO:365.2155; Found: 365.2156.

EXAMPLE 5501-(Cyclopropylmethyl)-4-(4'-(5"-tetrazolyl)phenoxymethyl)piperidine

A mixture of 1-(cyclopropylmethyl)-4-(4"-cyanophenoxy)methylpiperidine(Example 515, 0.75 g, 2.8 mmol), sodium azide (0.2 g, 3 mmol), ammoniumchloride (0.15 g, 3 mmol) and N,N-dimethylformamide (10 mL) was stirredat 100°-120° C. for 23 h. The excess solvent was distilled in vacuo; theresidue was suspended in water. A concentrated hydrochloride solutionwas added until pH=1. The solid formed was filtered, washed with waterand dried in vacuo. The title compound (100 mg) had the followinganalytical data: ¹ H-NMR (DMSO-d₆, 300 MHz): 7.9 (d, 2H, J=7), 7.0 (d,2H, J=7), 3.95 (d, 2H, J=6), 3.45 (br d, 2H, J=9), 2.9-2.75 (m, 3H),2.1-1.9 (m, 3H), 1.7-1.5, (m, 2H), 1.1-1.0 (m, 1H), 0.7-0.6 (m, 2H),0.45-0.3 (m, 2H); MS:313.

EXAMPLE 551 1-(t-Butyldimethylsilyloxy)-4-(4'-methoxyphenyl)benzene

A solution of 4-bromoanisole (1.87 g, 10 mmol) in dry tetrahydrofuran(20 mL) was cooled to -78° C. with stirring under a nitrogen atmosphere.A solution of t-butyl lithium in pentane (1.7 M, 11.8 mL, 20 mmol) wasadded dropwise. The reaction mixture was stirred at -78° C. for 1 h. Asolution of freshly-fused zinc chloride (2.04 g, 15 mmol) in drytetrahydrofuran (20 mL) was added; the reaction mixture was warmed to-20° C. over 20 min, then cooled to -78° C. A solution of1-bromo-4-t-butyl-dimethylsilyloxybenzene (2.86 g, 10 mmol) in drytetrahydrofuran (10 mL) was added, followed by tetrakis(triphenylphosphine)palladium (0) (1.15 g, 1 mmol). The reaction waswarmed to 50° C. and stirred for 21 h. The reaction mixture was pouredonto a saturated NH₄ Cl solution and extracted three times with ethylacetate. Drying over magnesium sulfate, filtration and removed in vacuoafforded the crude product.

Column chromatography, first with ethyl acetate-hexanes (1:9), thenhexanes, afforded the title compound, a solid (2.2 g): ¹ H-NMR (CDCl₃,300 MHz): 7.45 (d, 2H, J=8), 7.4 (d, 2H, J=8), 6.95 (d, 2H, J=B), 6.9(d, 2H, J=8), 3.85 (s, 3H), 1.0 (s, 9H), 0.25 (s, 6H). The product wasstill contaminated with trace amounts of triphenylphosphine and startingsilyl ether.

EXAMPLE 552 1-(t-Butyldimethylsilyloxy)-4-(4'-methylthiophenyl)benzene

Using the procedure described for Example 551, 4-bromothioanisole (2.03g, 10 mmol) was converted to the title compound, a solid (0.51 g): ¹H-NMR (CDCl₃, 300 MHz): 7.5 (d, 2H, J=8), 7.45 (d, 2H, J=8), 6.9 (d, 2H,J=8), 6.7 (d, 2H, J=8), 2.5 (s, 3H), 1.0 (s, 9H), 0.2 (s, 6H). Thisproduct was also contaminated with triphenylphosphine and startingbromide.

EXAMPLE 553 1-(t-Butyldimethylsilyloxy)-4-(4'-fluorophenyl)benzene

Using the procedure described for Example 551, 4-bromofluorobenzene(1.75 g, 10 mmol) was reacted to give the title compound (2.94 g): ¹H-NMR (CDCl₃, 300 MHz): 7.5 (dd, 2H, J=8,6), 7.4 (d, 2H, J=8), 7.1 (brt, 2H, J=8), 6.9 (d, 2H, J=8), 6.7 (d, 2H, J=8), 1.0 (s, 9H), 0.25 (s,6H). This product was contaminated with triphenylphosphine and startingsilyl ether.

EXAMPLE 554 Ethyl-4-(4'-fluorophenyl)benzoate

Using the procedure of Example 551, 4-bromofluorobenzene (1.75 g, 10mmol) was metallated and coupled with ethyl 4-bromobenzoate (2.28 g, 10mmol) to give the title compound after chromatography (ethylacetate-hexanes (1:9) (0.7 g)): ¹ H-NMR (CDCl₃, 300 MHz): 8.1 (d, 2H,J=8), 7.65-7.5 (m, 4H), 7.15 (t, 2H, J=8), 4.4 (q, 2H, J=7), 1.4 (t, 3H,J=7); MS:244.

Examples 555 through 557 were prepared according to the methodsdescribed for Example 1A (Table 19).

                  TABLE 19                                                        ______________________________________                                         ##STR37##                                                                    Ex.     R          m       bp (°C.)                                    ______________________________________                                        555     2-CH.sub.3 0       145-150 (0.5 mm Hg) (a)                            556     2,2-Cl.sub.2 -1-CH.sub.3                                                                 0       (b)                                                557     H          1       145-150 (0.2 mm Hg) (c)                            ______________________________________                                         Footnotes for Table 19                                                        (a) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 4.7-4.5(m, 1H), 4.3-4.1(m, 1H),         3.6-3.4(m, 2H), 3.1(br t, 1H, J=7), 2.6(br t, 1H, J=7), 2.0-1.6(m, 5H),       1.5-1.0(m, 4H), 1.1(d, 3H, J=7), 0.65-0.55(m, 1H); MS: 197.                   (b) mp=105-107° C.; .sup.1 HNMR(CDCl.sub.3, 300 MHz): 4.6(br t, 1H     J=7), 3.95(br t, 1H, J=7), 3.6-3.5(m, 2H), 3.25(m, 1H), 2.8-2.6(m, 1H),       2.1-1.7(m, 6H), 1.55(d, 3H, J=7), 1.5-1.1(m, 2H); MS: 265.                    (c) .sup.1 HNMR(CDCl.sub.3, 300 MHz): 4.65(br d, 1H, J=10), 3.9(br d, 1H,     J=10), 3.55-3.45(m, 2H), 3.1-2.9(m, 2H), 2.65-2.5(m, 1H), 2.3(d, 2H, J=7)     2.0-1.6(m, 4H), 1.3-1.0(m, 4H).                                          

UTILITIES SECTION

The compounds of this invention and their pharmaceutically acceptablesalts possess psychotropic properties, particularly antipsychoticactivity of good duration with selective sigma receptor antagonistactivities while lacking the typical movement disorder side-effects ofstandard dopamine receptor antagonist antipsychotic agents. Thesecompounds may also be useful as antidotes for certain psychotomimeticagents such as phencyclidine (PCP), and as antidyskinetic agents.

IN VITRO Sigma Receptor Binding Assay

Male Hartley guinea pigs (250-300 g, Charles River) were sacrificed bydecapitation. Brain membranes were prepared by the method of Tam (Proc.Natl. Acad. Sci. USA 80: 6703-6707, 1983). Whole brains were homogenized(20 seconds) in 10 vol (wt/vol) of ice-cold 0.34 M sucrose with aBrinkmann Polytron (setting 8). The homogenate was centrifuged at 920×gfor 10 minutes. The supernatant was centrifuged at 47,000×g for 20minutes. The resulting membrane pellet was resuspended in 10 vol(original wt/vol) of 50 mM Tris HCl (pH 7.4) and incubated at 37° C. for45 minutes to degrade and dissociate bound endogenous ligands. Themembranes were then centrifuged at 47,000×g for 20 minutes andresuspended in 50 mM Tris HCl (50 mL per brain).

0.5 mL aliquots of the membrane preparation were incubated withunlabeled drugs, 1 nM (+)-[³ H] SKF 10,047 in 50 mM Tris HCl, pH 7.4, ina final volume of 1 mL. Nonspecific binding was measured in the presenceof 10 μM (+)-SKF 10,047. The apparent dissociation constant (Kd) for(+)-[³ H]SKF 10,047 is 50 nM. After 45 minutes of incubation at roomtemperature, samples were filtered rapidly through Whatman GF/C glassfilters under negative pressure, and washed 3 times with ice-cold Trisbuffer (5 mL).

IC₅₀ s were calculated from log-logit plots. Apparent K_(i) s werecalculated from the equation, K_(i) =IC₅₀ /[1+(L/K_(d))] (4), where L isthe concentration of radioligand and K_(d) is its dissociation constant.Data are shown in Table I.

DOPAMINE RECEPTOR BINDING

Membranes were prepared from guinea pig striatum by the method describedfor sigma receptor binding. The membranes were then resuspended in 50 mMTris HCl (9 mL per brain).

0.5 mL aliquots of the membrane preparation were incubated withunlabeled drugs, and 0.15 nM [³ H]spiperone in a final volume of 1 mLcontaining 50 mm Tris HCl, 120 MM NaCl and 1 mM MgCl₂ (pH 7.7).Nonspecific binding was measured in the presence of 100 nM(+)-butaclamol. After 15 minutes of incubation at 37° C., samples werefiltered rapidly through Whatman GF/C glass filters under negativepressure, and washed three times with ice-cold binding buffer (5 mL).

IC₅₀ s were calculated from log-logit plots. Apparent K_(i) s werecalculated from the equation K_(i) =IC₅₀ [1+(L/K_(d))](4), where L isthe concentration of radioligand and K_(d) is its dissociation constant.Data are shown in Table I.

The data in Table I indicate that haloperidol, a typical antipsychoticdrug, has potent binding affinity for both the sigma and dopaminereceptors. This binding profile of haloperidol reflects the therapeuticactivity as well as the motor side effects caused by antagonism of thedopamine receptors. In contrast, the examples of this invention shown inTable I indicate potent and selective binding affinity for sigmareceptors without binding to the dopamine receptors. Therefore thesecompounds are not expected to produce the extrapyramidal symptoms thatare typical of that produced by haloperidol and other typicalantipsychotics that are dopamine receptor antagonists.

IN VIVO Isolation-Induced Aggression in Mice

This is a modification of the method of Yen et al. (Arch. Int.Pharmacodyn. 123: 179-185, 1959) and Jannsen et al. (J. Pharmacol. Exp.Ther. 129: 471-475, 1960). Male Balb/c mice (Charles River) were used.After 2 weeks of isolation in plastic cages (11.5×5.75×6 in) the micewere selected for aggression by placing a normal group-housed mouse inthe cage with the isolate for a maximum of 3 minutes. Isolated micefailing to consistently attack an intruder were eliminated from thecolony.

Drug testing was carried out by treating the isolated mice with testdrugs or standards. Fifteen minutes after dosing with test drugs by theoral route, one isolated mouse was removed from its home cage and placedin the home cage of another isolate. Scoring was a yes or no responsefor each pair. A maximum of 3 minutes was allowed for an attack and thepair was separated immediately upon an attack. Selection of home cageand intruder mice was randomized for each test. Mice were treated andtested twice a week with at least a 2 day washout period betweentreatments.

As shown in Table II, haloperidol and Examples 1, 228, 409, 493 and 494all have potent activities in inhibiting the isolation-inducedaggressive behavior indicating psychotropic activities.

PCP-INDUCED TURNING BEHAVIOR IN RATS

Male Sprague-Dawley rats (CD/CR, Charles River), weighing 190-290 g,were used for surgery. In order to spare nonadrenergic neurons, ratswere injected with 25 mg/kg imipramine i.p. 30 minutes before surgery.The rats were anesthetized with a 1:1.2 ratio mixture ofXylazine:Ketamine given 0.1 mL/100 g body weight i.m. A Ringers-Wydaze(100:0.01) solution was given to prevent dehydration. Dopamine wasdepleted in the right striatum by injecting the neurotoxin6-hydroxydopamine (6-OHDA) into the substantia nigra of the rightcerebral hemisphere. Five mg of 6-OHDA was dissolved in 5 mL of a 0.04%ascorbic acid solution which had been deoxygenated with nitrogen. FiveμL of the 6-OHDA solution was injected into the substantia nigra througha 26 gauge needle over a five minute period. Stereotaxic injectioncoordinates were -2.5 mm posterior to bregma, -2.1 mm right of themidsagittal suture, and -8.6 mm below the skull surface with the incisorbar set at +5.0 mm. Following surgery they were given 10 days to recoverwhile housed four per cage (45.0 L×20.0 H×26.0 W) with ALPHA-dri beddingand ad lib access to Pro-Lab rodent chow and deionized water. Followingrecovery, the wood clips were removed, the rats were individually housedin suspended cages, and they were placed on a restricted diet so thattheir weight did not exceed 375 g. At all times they were housed in theanimal care facility under a 12--12 hour light/dark cycle (light on at6:00 h, light off at 18:00 h).

Rotation rate and direction were determined with Coulbourn InstrumentsRotometry Monitors. Clockwise and counter clockwise rotations wererecorded at 30 and 60 minute intervals. The rats were examined forcorrect lesion location by testing for rotational activity induced bys.c. injections of 3.0 mg/kg D-amphetamine SO₄, and 2.0 mg/kg PCP HCl,respectively. These drugs were administered in the following sequence:Amphetamine was given 30 second before testing. Seven days later, therats were injected with PCP 30 seconds before testing. Only those ratswith an ipsilateral rotation rate of 2.5 turns per minute or higher wereused in subsequent tests.

Methocel® or test drugs were administered by the oral route (p.o.) 20minutes before testing. Phencyclidine (1.5 mg/kg) was given s.c.immediately before testing.

The data were analyzed with an analysis of variance statistical test andindividual comparisons of each dose of test drug to control were madewith Dunnett's multiple range test. The ED50 was calculated with aLitchfield and Wilcoxon test using percent of control values. Data areshown in Table III.

INDUCTION OF CATALEPSY

This is a modification of the method of Costall and Naylor(Psychopharmacologia (Berl.), 43, 69-74, 1975). Male CD rats (CharlesRiver) weighing 250-300 g were treated with test drugs and standards bythe oral route and tested for the presence of catalepsy 30 minute, 60minute, and 90 minute after treatment. To test for catalepsy, each ratis placed with its front paws over a 10 cm high horizontal bar. Theintensity of catalepsy is measured by the length of time it takes theanimal to move both forelegs to the table. A time of 20 seconds isconsidered maximal catalepsy. Data is shown in Table III.

As shown in Table III, both haloperidol and Example 494 have potentactivity in inhibiting the potent hallucinogen PCP-induced turningbehavior in rats, supporting their use for treatment of psychosis. Inthe catalepsy test which is a model for extrapyramidal symptoms,haloperidol is very potent in producing catalepsy and this agrees wellwith the side-effect profile of haloperidol in the clinic. In contrast,Example 494 does not produce catalepsy and suggests very low potentialfor extrapyramidal symptoms and tardive dyskinesia.

                  TABLE I                                                         ______________________________________                                        Receptor Binding Affinity                                                     Example          Sigma       (D-2)                                            ______________________________________                                        Haloperidol      +++         +++                                               1               +++         -                                                230              +++         -                                                233              ++          -                                                234              +++         -                                                240              ++          -                                                411              +++         -                                                412              +++         -                                                413              ++          -                                                416              +++         -                                                435              +++         -                                                442              ++          -                                                504              +++         -                                                505              ++          -                                                506              ++          -                                                544              ++          -                                                539              +           -                                                541              ++          -                                                542              +++         -                                                543              +           -                                                547              +++         -                                                548              +++         +                                                545              +           -                                                546              +++         -                                                549              +           -                                                420              +++         -                                                421              +++         -                                                422              ++          -                                                423              +++         -                                                323              +           -                                                326              ++          -                                                424              +++         +                                                425              +++         -                                                525              +++         +                                                515              +++                                                          516              +++         -                                                511              +           -                                                509              +++         -                                                533              +           -                                                532              ++          -                                                530              +++         -                                                ______________________________________                                    

                  TABLE II                                                        ______________________________________                                                        In Vivo Inhibition of                                         Example         Isolation-induced Aggression                                  ______________________________________                                        Haloperidol     +++                                                            1              ++                                                            230             +++                                                           411             +                                                             503             +++                                                           504             +++                                                           ______________________________________                                    

                  TABLE III                                                       ______________________________________                                                     In Vivo Inhibition of                                            Example      PCP-induced Turning                                                                            Catalepsy                                       ______________________________________                                        Haloperidol  +++              +++                                             504          +++              -                                               ______________________________________                                    

DOSAGE FORMS

Daily dosage ranges from 1 mg to 2000 mg. Dosage forms (compositions)suitable for administration ordinarily will contain 0.5-95% by weight ofthe active ingredient based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions; it can also be administeredparenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, sucrose, mannitol, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric-coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

What is claimed is:
 1. A method of treating physiological or druginduced psychosis or dyskinesia in a mammal comprising administering tothe mammal an antipsychotic or antidyskinetic effective amount of acompound of having the formula: ##STR38## or a pharmaceuticallyacceptable salt thereof, wherein: m is 0 to 3;n is 0 to 3; provided mand n are not both O; p is 0 to 3; X is O, S, SO, SO₂, NR⁶ or CO; R¹ R³,and R⁷ independently are H, alkyl of 1 to 5 carbon atoms, halogen, NR¹⁰R¹¹, OH, CO₂ H, carboalkoxy of 2 to 6 carbon atoms, CN, Ar¹, alkoxy of 1to 5 carbon atoms or alkylthio of 1 to 5 carbon atoms; R², R⁴ and R⁸independently are H, alkyl of 1 to 5 carbon atoms, carboalkoxy of 2 to 6carbon atoms, CN, alkoxy of 1 to 5 carbon atoms or Ar¹ ; provided thatR¹, R², R³ and R⁴ are not alkoxy of 1 to 5 carbon atoms, alkylthio of 1to 5 carbon atoms, NR¹⁰ R¹¹ or OH when X is O, S, SO, SO₂ or NR⁶ ; R⁵ isH, alkyl, halogen, OH or alkenyl; R⁶ is H, alkyl of 1 to 5 carbon atomsor Ar¹ ; Ar and Ar¹ independently are naphthyl, pyridyl, pyrimidyl,indolyl, quinolinyl, isoquinolinyl, or phenyl optionally substitutedwith alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, SH, S(O)_(t)alkyl of 1 to 3 carbon atoms, where t is 1, 2 or 3, dialkylamino of 2 to6 carbon atoms, halogen, OH, alkylamino of 1 to 3 carbon atoms, NH₂, CN,NO₂, SO₃ H, tetrazole, CO₂ H, carboalkoxy of 2 to 6 carbon atoms, CONH₂,SO₂ NH₂, COR⁹, CONR¹² R¹³, SO₂ NR¹² R¹³, Ar², OAr² or SAr² ; Ar² isnaphthyl or phenyl optionally substituted with alkyl of 1 to 3 carbonatoms, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, alkoxyof 1 to 3 carbon atoms, halogen or alkylthio of 1 to 3 carbon atoms; R⁹,R¹⁰, R¹¹, R¹² and R¹³ independently are H, alkyl of 1 to 5 carbon atomsor phenyl or R¹⁰ and R¹¹ taken together are an alkylene chain of 3 to 6carbon atoms or R¹² and R¹³ taken together are an alkylene chain of 3 to6 carbon atoms; and a or b is a double bond or a single bond, providedthat both are not double bonds.
 2. A method of claim 1 wherein X is COor O.
 3. A method of claim 1 wherein m is O.
 4. A method of claim 1wherein n and p are each
 1. 5. A method of claim 1 wherein R³ -R⁵ are H.6. A method of claim 1 wherein Ar is phenyl optionally substituted withhalogen, OCH₃, NH₂, NO₂ or another phenyl group.
 7. A method of claim 1wherein:X is CO or O; m is 0; n and p are each 1; R³ -R⁵ are H; and Aris phenyl optionally substituted with halogen, OCH₃, NH₂, NO₂ or anotherphenyl group.
 8. A method of claim 7 wherein X is CO.
 9. A method ofclaim 7 wherein Ar is 4-fluorophenyl.
 10. A method of claim 7 wherein:Xis CO; n and p are each 1; R³, R₄ and R⁵ are H; and Ar is4-fluorophenyl.
 11. A method of claim 7 wherein X is O.
 12. A method ofclaim 7 wherein:X is O; m is 0; n and p are each 1; R³, R⁴ and R⁵ are H;and Ar is 4-fluorophenyl.
 13. A method of claim 1 wherein the compoundis 1-(cyclopropyl methyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine.
 14. A method of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl) piperidine,hydrobromide salt.
 15. A method of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4"-chlorophenyl)-2'-oxoethyl) piperidine.16. A method of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4"-chlorophenyl)-2'-oxoethyl) piperidine,hydrobromide salt.
 17. A method of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4'-fluorophenoxyphenyl) piperidine.
 18. Amethod of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4'-fluorophenoxyphenyl) piperidine,hydrochloride salt.
 19. A method of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4'-chlorophenoxymethyl)piperidine.
 20. Amethod of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4'-chlorophenoxymethyl)piperidine,hydrochloride salt.
 21. A method of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4'-nitrophenoxymethyl) piperidine.
 22. Amethod of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4"-biphenyl)-2'-oxoethyl)piperidine.
 23. Amethod of claim 1 wherein the compound is1-(cyclopropylmethyl)-4-(2'-(4"-biphenyl)-2'-oxoethyl))piperidine,hydrobromide salt.
 24. A method of claim 1 wherein X is O, S, SO, SO₂,NR⁶, or CO.
 25. A method of treating physiological or drug inducedpsychosis or dyskinesia in a mammal by inhibition of the sigma receptorcomprising administering to the mammal an antipsychotic orantidyskinetic effective amount of a compound of having the formula:##STR39## or a pharmaceutically acceptable salt thereof, wherein: m is 0to 3;n is 0 to 3; provided m and n are not both O; p is 0 to 3; X is O,S, SO, SO₂, NR⁶. CR⁷ R⁸, CO, or CHOH; R¹ R³, and R⁷ independently are H,alkyl of 1 to 5 carbon atoms, halogen, NR¹⁰ R¹¹, OH, CO₂ H, carboalkoxyof 2 to 6 carbon atoms, CN, Ar¹, alkoxy of 1 to 5 carbon atoms oralkylthio of 1 to 5 carbon atoms; R², R⁴ and R⁸ independently are H,alkyl of 1 to 5 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, CN,alkoxy of 1 to 5 carbon atoms or Ar¹ ; provided that R¹, R², R³ and R⁴are not alkoxy of 1 to 5 carbon atoms, alkylthio of 1 to 5 carbon atoms,NR¹⁰ R¹¹ or OH when X is O, S, SO, SO₂ or NR⁶ ; R⁵ is H, alkyl, halogen,OH or alkenyl; R⁶ is H, alkyl of 1 to 5 carbon atoms or Ar¹ ; Ar and Ar¹independently are naphthyl, pyridyl, pyrimidyl, indolyl, quinolinyl,isoquinolinyl, or phenyl optionally substituted with alkyl of 1 to 3carbon atoms, alkoxy of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbonatoms and 1 to 7 halogen atoms, SH, S(O)_(t) alkyl of 1 to 3 carbonatoms, where t is 1, 2 or 3, dialkylamino of 2 to 6 carbon atoms,halogen, OH, alkylamino of 1 to 3 carbon atoms, NH₂, CN, NO₂, SO₃ H,tetrazole, CO₂ H, carboalkoxy of 2 to 6 carbon atoms, CONH₂, SO₂ NH₂,COR⁹, CONR¹² R¹³, SO₂ NR¹² R¹³, Ar², OAr² or SAr² ; Ar² is naphthyl orphenyl optionally substituted with alkyl of 1 to 3 carbon atoms,haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, alkoxy of 1to 3 carbon atoms, halogen or alkylthio of 1 to 3 carbon atoms; R⁹, R¹⁰,R¹¹, R¹² and R¹³ independently are H, alkyl of 1 to 5 carbon atoms orphenyl or R¹⁰ and R¹¹ taken together are an alkylene chain of 3 to 6carbon atoms or R¹² and R¹³ taken together are an alkylene chain of 3 to6 carbon atoms; and a or b is a double bond or a single bond, providedthat both are not double bonds.